Pulmonary Involvement in Patients with Hematological Malignancies

Pulmonary Involvement in Patients with Hematological Malignancies

 

Élie Azoulay (Editor)

Pulmonary Involvement in Patients with Hematological Malignancies

Editor Élie Azoulay, M.D., Ph.D Service de Réanimation Médicale Hôpital Saint-Louis 1 avenue Claude Vellefaux, 75010, Paris France and Medical Intensive Care Units, Saint-Louis Hospital, Paris 7 University, Paris France [email protected]

ISBN  978-3-642-15741-7 e-ISBN  978-3-642-15742-4 DOI  10.1007/978-3-642-15742-4 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2011921694 © Springer-Verlag Berlin Heidelberg 2011 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: eStudioCalamar, Figueres/Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

This book is dedicated to all patients: you are the force that drives our work and our most important teachers. Thank you. I would like to dedicate this book to all those who are important to me.

 

Foreword I

In the United States, cancer is the second most common cause of death. Over 560,000 people die of cancer each year. One in four deaths in the United States is due to cancer. Since the 1970s, the 5-year survival from cancer has increased from 50% to 66%. This improvement in survival reflects earlier diagnosis and more effective therapies and management strategies. As medical technology improves, even more progress is anticipated, but such progress requires experience and analysis, which only highly experienced clinicians and scientists can amass. Patients with hematologic malignancies are a special challenge to health care providers. In the United States, over 130,000 persons are diagnosed with a hematologic malignancy each year, and over 50,000 individuals die. Half of these hematologic malignancies are acute or chronic leukemias, and the remainder is primarily lymphomas or multiple myeloma. These hematologic malignancies represent 9.5% of the cancer burden in the United States. These patients undergo a wide variety of immunosuppressive therapies that can have impressive results in terms of disease-free survival. However, the toxicities of these regimens can be substantial. Both disease and therapy can cause complications. These complications are very different for different cancers and for different therapies. Our ability to improve the outcome of hematologic malignancies is due to more precise methods to identify the specific malignant process and to an expanding array of treatments for the underlying malignancies. These treatments are often used in combination regimens over periods of many months to years. These treatments include ionizing radiation, cytotoxic drugs, immunosuppressive agents, and stem cell transplantation. There are now over 50 drugs approved in the United States to treat hematologic malignancies. These drugs have an expanding number of mechanisms of action, ranging from traditional cytotoxic agents to newer drugs that are enzyme inhibitors, monoclonal antibodies, or proteasome inhibitors. Each of these approaches offers promise for specific indications, but also produces enormous complexity in terms of the effects on host immune and inflammatory response, and in terms of the specific organ toxicities they produce. In this book, Pulmonary Involvement in Patients with Hematological Malignancies, Élie Azoulay has assembled experienced clinicians from around the world to focus on the infectious and non-infectious pulmonary complications that occur in these patients as they are managed with these diverse therapeutic modalities. Dr. Azoulay is renowned for his experience in dealing with such complications and for his careful investigations, which have improved patient care around the world. He has assembled



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Foreword I

well-published authorities to provide a comprehensive body of information on epidemiology, natural history, diagnosis, and therapy of pulmonary complications. What makes this book especially useful is the focus on very specific clinical scenarios. Clinicians who care for patients with hematologic malignancies, which includes most oncologists, infectious disease specialists, and pulmonary-critical care physicians, will immediately be drawn to chapters on long-standing clinical controversies such as the role for various types of lung biopsies, new molecular techniques to enhance diagnostic accuracy, and chapters on specific pathogens such as Candida, Aspergillus, and CMV. Also of special note are chapters that focus on non-infectious challenges such as diffuse alveolar hemorrhage and transfusion-related lung injury. Dr. Azoulay has also included chapters on management problems, such as invasive and non-invasive ventilation, transfusion policies, and palliative care, which clinicians will benefit from reviewing in order to be certain they are providing state-of-the-art care. This book represents the work of experienced, thoughtful, evidence-based clinicians who provide the authoritative information that only a highly specialized, focused book such as this can supply. Health care providers who deal with this patient population will find the information and insights in this volume to be extremely valuable and will refer to this book often! H. Masur

Foreword II

The number of immunocompromised patients has increased over the last decade. Improvements in solid-organ and hematopoietic stem cell transplantation techniques, the expanded use of chemotherapy and steroid use, and the appearance of immunomodulatory therapies are some of the reasons that explain this increase. The success of the different transplant techniques has generated a great deal of interest in the management of immunocompromised patients among clinicians and basic scientists. The recognition and management of pulmonary complications that result from immunosuppression are challenging tasks. The lungs may be injured directly through infectious or toxic insults. Conversely, lung disease may result as a secondary event. Pulmonary complications in these patients require a multidisciplinary approach that often involves different specialties. This includes an appreciation of the epidemiology of post-transplant pulmonary complications, the different diagnoses for these processes, the appropriate diagnostic explorations, and the specific treatments and potential interactions. Some of these patients with pulmonary complications may need intensive care treatment. The first part of this book is dedicated to non-infectious complications. Dr. Bekele Afessa describes the epidemiology, diagnosis, and treatment of diffuse alveolar hemorrhage, which is a frequent entity in hematological patients. Dr. Afessa provides a very comprehensive review of non-infectious pulmonary involvement after hematopoietic stem cell or bone marrow transplantation. The non-infectious complications comprise a series of entities that may respond to steroid treatment, although in some cases, they will lead to fatal outcomes (graft-versus-host disease). Pulmonary veno-occlusive disease following hematopoietic stem cell transplantation is a rare complication that is difficult to manage. This subject is reviewed in depth by Drs. Bunte and Burns. Not infrequently, drugs used to treat cancer patients have cardiovascular complications. One chapter describes how frequently these complications occur, which drugs may be responsible, and how we can decrease the severity of cardiovascular toxicity caused by these drugs. Diagnosis of pulmonary infiltrates in hematologic malignancies is a difficult problem that often requires bronchoscopic evaluation. Post-mortem studies have helped us to provide the operative values of the techniques that we use in vivo. Dr. Pastores and colleagues have written a comprehensive chapter on this subject. Hematologic malignancies often require transfusions that may be followed by acute lung injury, especially in children. Respiratory infections in patients with hematologic malignancies, neutropenia, and bone marrow transplants continue to be a



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serious problem triggered by abnormalities in the function and number of neutrophils, T and B lymphocytes, anatomic considerations, or a combination of factors. They range from bacterial pneumonias to opportunistic infections. Dr. Soubani et al. provide an update on the etiology, epidemiology, diagnosis, and management of these infections. In summary, this book edited by Dr. Élie Azoulay gathers a series of excellent chapters written by experts in different problems that cause acute lung injury in hematological patients. The book will be very useful for specialists dealing with these types of problems, and this obviously includes intensive care physicians. Prof. Antoni Torres

Acknowledgments

I am grateful to all the authors and co-authors who contributed to this book, spending their valuable time to write thoughtful presentations of difficult topics based on their own clinical experience acquired over the years and on a thorough knowledge of the most recent literature. Many thanks to all of you. I have the deepest respect and consideration for the team working at the medical ICU at the Saint-Louis Hospital. Along with Benoit Schlemmer, I know how lucky we are to work with this group of people who care deeply about their patients and about communicating their skills to their young colleagues. They gladly accept the challenges raised by the sickest patients, while making every effort to avoid nonbeneficial care. I learn everyday from them. I am indebted to the hematologists who work closely with our medical ICU at the Saint Louis Hospital. We learn a lot from each other as we combine our energies to devise the best means of caring for our patients. Our close collaboration has nourished important research projects, shedding new light on topics such as the mechanisms underlying specific organ dysfunctions, emerging infections, and unexpected drug-related toxicities. This new understanding has helped us to improve patient outcomes. I am grateful to Dr Francois Vincent for his critical revision of contributions to this book and his willingness to check every single reference. The huge amount of work he put into this book was invaluable. I owe a debt of gratitude to Meike Stoeck from Springer for her assistance and willingness to adjust to my own pace, as well as to Ute Heilmann for her trust and kindness. I have a personal thought for Dr Arnaud de Lassence who would certainly have written a contribution for this book. He was among those who knew the most about pulmonary involvement in patients with hematological malignancies. The memory of his bright mind and sparkling enthusiasm continues to nourish my work.



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Contents

Part I  Preamble and Introduction   1 Managing Patients with Hematological Malignancies for 25 Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Benoit Schlemmer

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  2 Pulmonary Involvement in Patients with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Élie Azoulay

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  3 Respiratory Infections in Patients with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ayman O. Soubani

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Part II  Epidemiology



  4 Epidemiology of Respiratory Events in Patients with HM (Not Including ICU) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Georg Maschmeyer

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  5 Epidemiology of Acute Respiratory Failure in Patients with HM (ICU Only) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carlos Agustí, Carmen Lucena, and Antoni Torres

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  6 Noninfectious Lung Involvement in Patients with Hematological Malignancies (Excluding BMT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bernard Maitre

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  7 Noninfectious Pulmonary Involvement in Hematopoietic Stem Cell or Bone Marrow Transplant Recipients . . . . . . . . . . . . . . . . . Bekele Afessa

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  8 Are There Any Pulmonary Issues Specifically Related to Cord Blood Transplants? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jonathan Gutman

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  9 Cardiovascular Complications of Cancer Therapeutics . . . . . . . . . . . . . Aarif Y. Khakoo and Callie S. Kwartler

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10 Prophylaxis: Peace of Mind? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 Benoit Guery and Karine Faure Part III  Diagnostic Strategy in HM Patients 11 How Type of Malignancy and Treatment Assist in the Etiological Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Alexandre Boyer and Didier Gruson 12 Contribution of Radiology in Patients with Hematological Malignancies and Pulmonary Involvement . . . . . . . . . . . . . . . . . . . . . . . 131 Claus Peter Heussel 13 Is There Still a Place for Transbronchial Lung Biopsy or Other Lung Biopsy Techniques? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Christophe Dooms and Vincent Ninane 14 The Increasing Role for Core Needle Biopsy of Pulmonary Lesions in Immunocompromised Patients . . . . . . . . . . . . . . . . . . . . . . . . 155 Cédric de Bazelaire, Raphael Calmon, Marion Chapelier, Amélie Pluvinage, and Eric de Kerviler 15 Minimally Invasive Diagnostic Strategy in Immunocompromised Patients with Pulmonary Infiltrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 Laurent Camous, Virginie Lemiale, Achille Kouatchet, David Schnell, Sandra de Miranda, and Élie Azoulay 16 Pleural Effusions and Thoracentesis in Patients with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Michael G. Alexandrakis, Paschalis Steiropoulos, and Demosthenes Bouros 17 Diagnostic Yield of BAL Fluid Cytology in Hematologic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 Jean-François Bernaudin and Jocelyne Fleury-Feith 18 New Methods for Bacterial Diagnosis in Patients with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 Agnès Ferroni and Jean-Ralph Zahar 19 FDG-PET Imaging in Haematological Patients with Pulmonary Infiltrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 Tomohiko Yamane

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20 What Has Been Learned from Postmortem Studies? . . . . . . . . . . . . . . . 243 Stephen M. Pastores, Alina O. Dulu, and Shilpa A. DeSouza Part IV  Lung Infections in Patients with HM 21 Common Viral Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257 David Schnell, Jérôme Legoff, and Élie Azoulay 22 Emerging Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 Oliver Schildgen 23 Cytomegalovirus Pneumonia in Patients with Hematologic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 Karen J. Vigil and Roy F. Chemaly 24 Herpes Simplex Virus Pneumonia in Patients with Hematologic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 Jharna N. Shah and Roy F. Chemaly 25 Pneumocystis Pneumonia in Non-AIDS Immunocompromised Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 Élie Azoulay, Virginie Lemiale, Achille Kouatchet, François Vincent, Antoine Roux, Guillaume Bollée, and Patricia Roux 26 Diagnosis of Invasive Pulmonary Aspergillosis in Patients with Hematologic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 Marie-Elisabeth Bougnoux, Fanny Lanternier, Emilie Catherinot, Felipe Suarez, and Olivier Lortholary 27 Emerging Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337 Marcia Garnica and Marcio Nucci 28 Candida Pneumonia in Patients with Hematological Neoplasia . . . . . . . 349 Carlos Carvajal, Jordi Rello, and Jeffrey Lipman 29 Parasitic Lung Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357 Jean-François Timsit, Jean-Paul Brion, and Hervé Pelloux 30 Pulmonary Mycobacterial Infections in Patients with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 Khalid A. Al-Anazi and Asma M. Al-Jasser Part V  Noninfectious Pulmonary Involvement in Patients with HM 31 Pleuropulmonary Changes Induced by Drugs in Patients with Hematologic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 Philippe Camus

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32 Cardiovascular Complications of Cancer and Radiation Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425 Callie S. Kwartler and Aarif Y. Khakoo 33 Diffuse Alveolar Hemorrhage in Hematopoietic Stem Cell Transplant Recipients and Patients with Hematologic Malignancy . . . . . 437 Bekele Afessa 34 Venous Thromboembolism in Patients with Hematologic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449 Tarek Sousou and Alok A. Khorana 35 Transfusion-Related Acute Lung Injury in Children with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 Rachel S. Bercovitz, J. Bradley Ball, Marguerite R. Kelher, and Christopher C. Silliman 36 Acute Respiratory Distress Syndrome (ARDS) in Neutropenic Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477 Mokart Djamel, Textoris Julien, Ettori Florence, Bruno Chetaille, and Blache Jean-Louis 37 Pulmonary Venoocclusive Disease Following Hematopoietic Stem Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491 Matthew C. Bunte and Linda J. Burns 38 Radiation Pneumonitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499 Miguel Gallego Díaz and Jordi Rello Condomines 39 Leukostasis, Infiltration and Pulmonary Lysis Syndrome Are the Three Patterns of Leukemic Pulmonary Infiltrates . . . . . . . . . . 509 François Vincent 40 Pulmonary MALT Lymphoma: Clinical, Molecular and Therapeutic Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521 Marie Wislez, Raphael Borie, Catherine Thieblemont, Marie-France Carette, Martine Antoine, and Jacques Cadranel 41 ARDS During Neutropenia Recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533 Élie Azoulay, Eric Ezingeard, Choupi-Salomon Berckowski, and Michael Darmon 42 Fibrosing Alveolitis in Hematologic Malignancy Patients Undergoing Hematopoietic Cell Transplantation . . . . . . . . . . . . . . . . . . 537 Huda Salman, Kenneth R. Cooke, and Hillard M. Lazarus

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Part VI Treatment and Difficult Decisions in Patients with HM and ARF 43 Antibiotic Therapy in Neutropenic Patients . . . . . . . . . . . . . . . . . . . . . . . 553 Matthieu Legrand, Adeline Max, and Bertrand Gachot 44 Antifungal Therapy in Patients with Hematological Malignancies . . . . 569 Raoul Herbrecht and Yasmine Nivoix 45 Antiviral Agents in Patients with Hematological Malignancies and Acute Respiratory Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589 Michael Sandherr 46 Mechanical Ventilation in Patients with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597 Márcio Soares, Jorge I.F. Salluh, and Pieter O. Depuydt 47 Optimizing Noninvasive Ventilation in Hematological Patients with Acute Respiratory Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607 Gilles Hilbert 48 Noninvasive Ventilation to Ensure the Safety of Fiberoptic Bronchoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617 Massimo Antonelli, Giuseppe Bello, and Riccardo Maviglia 49 NIV Outside the ICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623 Stefano Nava and Sebastiano Mercadante 50 Palliative Noninvasive Mechanical Ventilation in Patients with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631 Anne-Pascale Meert, Thierry Berghmans, and Jean-Paul Sculier 51 Acute Kidney Injury in Cancer Patients . . . . . . . . . . . . . . . . . . . . . . . . . 637 Michael Darmon, Laurent Camous, Camille Devanlay, Emmanuel Canet, Benoit Schlemmer, and Fabrice Zeni 52 Septic Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651 David Grimaldi and Frédéric Pène 53 Prognostic Factors for Mortality in the Critically Ill Cancer Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665 Kathleen N.S. Cathcart and Jeffrey S. Groeger 54 Managing Critically Ill Cancer Patients: Another Medical Success Story . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671 Élie Azoulay, Marcio Soares, Michael Darmon, Dominique Benoit, Stephen Pastores, and Bekele Afessa

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55 Palliative Care and Dyspnea Management in Patients with Hematological Malignancies and Acute Respiratory Failure . . . . 683 Amy P. Abernethy, Jane L. Wheeler, and David C. Currow 56 End-of-Life Decisions in Cancer Patients . . . . . . . . . . . . . . . . . . . . . . . . . 693 Lieve Van den Block, Agnes van der Heide, and Luc Deliens Part VII  Pearls That You Should be Aware Of 57 An Unexpected Diagnosis of Pulmonary Tuberculosis . . . . . . . . . . . . . . 703 Virginie Lemiale, A. Seguin, and Élie Azoulay 58 Respiratory Symptoms Occurring 4 Months After Allogeneic Hematopoietic Stem Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . 707 Anne Bergeron, Séverine Feuillet, Véronique Meignin, Patricia Ribaud, and Abdellatif Tazi 59 Pulmonary Complications of Chronic Lymphocytic Leukemia . . . . . . . 715 Melhem Solh and Punit Wadhwa 60 Clinical Pearls: Pulmonary Veno-occlusive Disease . . . . . . . . . . . . . . . . 725 Jonathan Gutman 61 Cytarabine-Induced Pulmonary Toxicity in Leukemic Patients . . . . . . 729 Fabio Forghieri, Leonardo Potenza, Monica Morselli, Monica Maccaferri, Giuseppe Torelli, and Mario Luppi 62 Histoplasmosis in a Patient with Chronic Myelogenous Leukemia . . . . 735 Vincent Peigne, Benoît Schlemmer, and Olivier Lortholary 63 Pulmonary Toxicity of Imatinib and Other BCR-ABL Tyrosine Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741 François Vincent 64 Rituximab-Related Pulmonary Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . 751 Yair Herishanu, Chava Perry, and Aaron Polliack 65 Cardiogenic Causes of Respiratory Failure in Patients with Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759 Julien Maizel, Berengere Gruson, Jean-Pierre Marolleau, and Michel Slama 66 Pulmonary Alveolar Proteinosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 771 François Vincent, H. Tandjaoui, and P.Y. Brillet

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67 Pneumocystis jiroveci Pneumonia in a Patient with Diffuse Large B-Cell Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781 Hung Chang and Lee-Yung Shih 68 Pulmonary Infiltration in Anaplastic T-Cell Lymphoma . . . . . . . . . . . . 787 Christophe Cracco, Julien Mayaux, Sylvain Choquet, Catherine Beigelman, and Frédéric Charlotte 69 A Rapidly Reversible Cause of Pulmonary Embolism . . . . . . . . . . . . . . 793 Sophie Georgin-Lavialle, Élie Azoulay, Fabrice Zeni, and Michael Darmon 70 Hairy Cell Leukemia with Pulmonary Infiltrates . . . . . . . . . . . . . . . . . . 797 Virginie Lemiale, Véronique Meignin, and Élie Azoulay 71 Trichosporon asahii Infection in a Neutropenic Patient . . . . . . . . . . . . . 801 Djamel Mokart, Antoine Sannini, Jean-Paul Brun, Laurent Chow-chine, and Jean-Louis Blache Part VIII  Post Face 72 Who Is This Book for? Reserved to Highly Specialized Teams? . . . . . . 807 Laurent Brochard 73 Pulmonary Involvement in Patients with Hematological Malignancies: And Now? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809 Patricia Ribaud and Gérard Socié Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 811

 

Part Preamble and Introduction

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Managing Patients with Hematological Malignancies for 25 Years Benoit Schlemmer

Contents References............................................................................

B. Schlemmer  Department of Intensive Care Medicine, Saint-Louis Hospital, Paris, France and University Paris-Diderot, Paris, France e-mail: [email protected]

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In 1986, just 25 years ago, three reports were published by Laufe [1], Maunder [2] and Ognibene [3], focusing on the occurrence of Adult Respiratory Distress Syndrome in neutropenic patients. Hematological patients had just begun to be included in the field of diffuse alveolar damage and pulmonary critical care medicine. For many years, hematological patients were known to experience severe life-threatening conditions because of the course of their underlying disease or complications of therapy. Most of the latter were considered from infectious origin, resulting in sepsis, multiple organ failure and death. Doctors in the field of hematology or cancer were reluctant to admit such patients to the ICU, which was presumed to be futile because of poor results. Most intensivists agreed that this kind of patient was beyond any supportive care. Misknowledge about pathophysiology, concepts, diagnosis and therapy was equally distributed on both sides, in hematology and critical care. The flaws and fears were similar among these physicians. Progress in the field of critical care and respiratory medicine along with therapeutic advances in the field of cancer has progressively changed medical attitudes regarding patients’ medical presentations and the management of hematological patients with pulmonary disease. Medical teams in specialized centers have moved from “just say no” [4] to “consider saying yes” or “let’s perform a trial” [5]. Twenty-five years have been necessary to distinguish among multiple complex medical entities, to increase our knowledge regarding both hematological diseases and complications of therapy. The role of the malignant process and its specific impact on organs and functions, or complex side effects of therapy, such as endothelial damage related to antineoplastic drugs or immune consequences of transplantation, have been

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_1, © Springer-Verlag Berlin Heidelberg 2011

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recognized. In addition, great progress has been made in the field of therapy, resulting in new opportunities and hopes for many patients previously considered to have rapidly fatal diseases. In addition, better knowledge about critical care conditions and the impact of their management by intensivists has also resulted in new concepts and strategies. Where critical care physicians cooperate with their colleagues in hematological wards, they have developed new strategies regarding diagnosis and therapy. The respective benefits of invasive versus noninvasive diagnostic procedures have been discussed, along with the opportunity to use new diagnostic tools in the field of infection or lung injury, from inflammation to healing and fibrosis. Improvement in respiratory therapy, with the development of noninvasive ventilatory support and low tidal volume mechanical ventilation, has resulted in the opportunity to develop the concept of early management for many hematological patients with pulmonary disease before the occurrence of critical conditions, out of the scope of any hope. Medical benefit for patients has been the result of improvement in basic science, pathophysiology and nosology in pulmonary medicine and hematology. Accordingly, better knowledge, better diagnosis and therapeutic advances should result in better strategies and improved patient outcomes. Widening the field of  diagnostic and therapeutic tools in pulmonary medicine for hematological patients has highlighted the need for accurate medical decision-making, both from technical and ethical points of view. When faced with a patient with a history of hematological disease and pulmonary signs, one should now distinguish between several etiologies, choose a diagnostic strategy or empiric therapy, and discuss whether an invasive diagnostic procedure or ventilatory support would be valuable, taking into account probabilities, hope of reversibility, patient willingness and riskbenefit analysis. Intensive care therapy of hematological patients now has to be considered as a way to support critical conditions in order to allow diagnostic procedures and/or therapy to reverse such medical situations. Emergency decisions sometimes have to be made, including in non-specialized medical facilities, because of the great developments in ambulatory medicine for some hematological disorders. However, sometimes, withholding or withdrawal of some therapeutic options has to be discussed, as for

B. Schlemmer

many other patients in ICUs. The medical decision has to be based both on evidence, whenever possible, and experience. Better knowledge in the field of pulmonary involvement in hematological malignant diseases has pushed intensivists and physicians in hematology to share their experience and to provide new opportunities for their patients. This has also resulted in the need for additional research in this field, not only related to acute conditions and their management, but also to long-term outcomes and quality of life. This book will offer any intensivist, even non-specialized, and any physician in the field of hematology and cancer the opportunity to review 25 years of medical progress. Increasing medical knowledge would not only result in answers for hematological patients with pulmonary disease, but would also result in more comprehensive understanding, in new questions for the future and in the opening of new fields for medical research in which both intensivists and cancer physicians should cooperate. In this respect, this book is exemplary. I want to thank all the contributors who have accepted the task of summarizing their outstanding experience for young physicians who need to be educated in the field of such difficult medical conditions. I want to congratulate my young colleague and friend, Elie Azoulay, who is a masterpiece in clinical training and supervision at Saint-Louis Hospital, but also a leader in clinical research, for initiating this huge work and succeeding in the challenge of gathering the most influent specialists in this field of medical care.

References   1. Laufe MD, Simon RH, Flint A, Keller JB (1986) Adult respiratory distress syndrome in neutropenic patients. Am J Med 80:1022–1026   2. Maunder RJ, Hackman RC, Riff E et al (1986) Occurrence of the adult respiratory distress syndrome in neutropenic patients. Am Rev Respir Dis 133:313–316   3. Ognibene FP, Martin SE, Parker MM et  al (1986) Adult respiratory distress syndrome in patients with severe neutropenia. N Engl J Med 315:547–551   4. Carlon GC (1989) Just say no. Crit Care Med 17(1):106–107   5. Lecuyer L, Chevret S, Thiery G, Darmon M, Schlemmer B, Azoulay E (2007) The ICU trial: a new admission policy for cancer patients requiring mechanical ventilation. Crit Care Med 35(3):808–814

 

2

Pulmonary Involvement in Patients with Hematological Malignancies Élie Azoulay

Acute pulmonary events are among the most common complications in patients with hematological malignancies. These events often raise difficult diagnostic and therapeutic challenges. In this book, readers faced with these challenges will find a vast array of clinically relevant information contributed by physicians in many specialties who have acquired considerable experience over the years. Pulmonary complications in patients with hematological malignancies may be related to many factors, including infection, tissue invasion by the malignant cells, toxicity and immune deficiency related to the disease or treatments. The multiplicity of the possible etiologies and frequent presence of more than one etiology in a given patient create diagnostic conundrums. Importantly, an early accurate diagnosis is crucial to improve patient outcomes. This book provides practical guidance on untangling complex diagnoses and selecting optimal treatments. In addition to hematologists, intensivists, and pulmonologists, clinicians from many specialties may be called on to manage respiratory events in patients with hematological malignancies. This book was written to serve as an easily accessible source of information to primary-care physicians, emergencyroom physicians, intensivists and physicians working in internal medicine, infectious diseases or pulmonary care departments. Furthermore, the problems encountered in patients with hematological malignancies are relevant to all specialties where patients

É. Azoulay  Service de Réanimation Médicale, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010, Paris, France and Medical Intensive Care Units, Saint-Louis Hospital, Paris 7 University, Paris, France e-mail: [email protected]

require immunosuppressant treatments for systemic inflammatory diseases, including clinical immunology, rheumatology, hepatology, gastroenterology, nephrology, dermatology, neurology, and solid organ transplantation. This book has six parts. After an introduction by Dr Soubani, who presents a comprehensive overview of infectious etiologies of respiratory events in patients with hematological malignancies, the first part focuses on epidemiology. International leaders draw attention to important points such as the specificities of bone marrow transplant recipients and the possibility of non-infectious pulmonary involvement, most notably heart failure with pulmonary edema whose diagnostic and therapeutic management differ fundamentally from those of other etiologies of respiratory events in hematological patients. The second part addresses ongoing controversies about the best diagnostic strategies, which are largely fueled by the fast pace at which new diagnostic tools are being introduced. Renowned researchers discuss the latest information on the benefit/risk ratio of diagnostic tools ranging from the least invasive (clinical examination) to the most invasive (surgical lung biopsy). This careful attention to diagnostic tools is warranted, as mortality is higher when no cause to the respiratory symptoms is identified. In patients who are not receiving mechanical ventilation, noninvasive diagnostic testing may provide comparable diagnostic yields to those obtained using bronchoscopy with bronchoalveolar lavage. Attention is drawn to the valuable information that can be derived by the optimal use and interpretation of lung computed tomography. In the third and the fourth parts of this book, leading researchers describe the spectrum of pulmonary infections in hematological patients because of pathogens ranging from common bacteria to opportunistic pathogens, and the spectrum of

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_2, © Springer-Verlag Berlin Heidelberg 2011

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noninfectious causes, including drug-related toxicity, pulmonary embolism, diffuse alveolar hemorrhage, and alveolar proteinosis. The fifth part provides new insights into treatments and difficult decisions for patients with hematological malignancies. Contri­ butions from physicians in various specialties were assembled to shed light on the many facets of this topic. Opinion leaders provide recommendations on the use (or withdrawal) of various therapeutic strategies. Last, the sixth part presents 15 carefully selected case reports about clinical situations that are rare but important. The goal is to improve the diagnosis of rare but treatable conditions. For each clinical situation, a literature review is reported. These case reports may constitute valuable teaching material for discussing patients with unusual problems. The abundance of tables, figures, radiographs, and computed tomography scans in the book considerably enriches the written material. Three methods can be suggested for using this book. First, you can look up a clinical situation you are interested in (e.g., pneumonia in patients with chronic lymphocytic leukemia or pulmonary infiltrates at the earliest phase of acute leukemia). Second, you can look for the diagnostic strategy that is best for evaluating a clinical suspicion of infectious or noninfectious pulmonary involvement (e.g., induced sputum, transbronchial biopsy, or core needle biopsy). Third, you can find a description of the clinical picture related to a given form of pulmonary involvement or a given pathogen (e.g., Pneumocystis pneumonia, cytomegalovirus pneumonia, cardiogenic pulmonary edema, diffuse alveolar hemorrhage, or transfusion-related acute lung injury). These three methods can complement one another. Therapeutic alternatives are also available for all these situations. I hope this book will spread ten important messages. First, in patients with hematological malignancies who experience respiratory complications, treating every possible etiology is not the best way to ensure a favorable outcome. Instead, identifying the exact cause improves survival. Second, within the first few hours the most likely causes of the respiratory symptoms should be determined based on the clinical findings (see the DIRECT strategy) and recorded in the medical chart. Treatments appropriate for these causes should be given immediately, while waiting for the results of further investigations. Third, computed tomography may help to support a clinical suspicion

É. Azoulay

of an infectious or noninfectious cause and may also rule out a number of etiologies. However, computed tomography alone cannot establish a diagnosis. Furthermore, computed tomography should be performed only after a comprehensive clinical assessment, whose findings guide the choice of the imaging strategy. Fourth, not all patients are at risk for all the possible etiologies. Knowledge of the specific risk factors for each cause is crucial. For instance, the type of immune deficiency indicates which pathogens are most likely to cause pulmonary involvement. A discerning risk factor assessment may show that some patients are at very low risk for some causes. Fifth, two diagnoses, cardiogenic pulmonary edema and bacterial infections, should be considered in all patients at all times during the course of the hematological malignancy. Sixth, positive tests (e.g., cytomegalovirus antigen test, PCR test for Pneumocystis, or virological studies of nasopharyngeal swabs) must be interpreted with great caution. A positive test does not always mean that the disease is present. Furthermore, several causes may be present in combination. For instance, even when the bronchoalveolar lavage fluid indicates alveolar hemorrhage, infections (e.g., aspergillosis, Pseudomonas, Staphylococcus, and other causes of necrotizing pneumonia), and noninfectious disorders (e.g., cardiogenic pulmonary edema, leukemic infiltrates, and drug-related toxicity) must be ruled out before accepting a diagnosis of diffuse alveolar hemorrhage and initiating the specific treatment for this condition. Another important point is that negative results do not always exclude diagnoses, such as cytomegalovirus pneumonia, Pneumocystis pneumonia, or invasive aspergillosis. The few diagnostic tests whose negative predictive value is close to 100% (e.g., PCR test for Pneumocystis) are extremely valuable. Seventh, thrombocytopenia does not protect against the occurrence of thromboembolic events. Eighth, core needle biopsy performed by an experienced operator can provide valuable diagnostic information. As with all invasive procedures, the ICU may be the safest place to monitor the patients before and after core needle biopsy. Ninth, each new diagnostic method must be carefully evaluated in a group of unselected patients with hematological malignancies. The diagnostic performance characteristics must be reported, together with the prevalence of the disease in the study group. Tenth, managing patients with pulmonary events and

2  Pulmonary Involvement in Patients with Hematological Malignancies

hematological malignancies requires considerable clinical skill, close collaboration among medical specialties and with the laboratories, and easy access to the ICU. Among patients with hematological malignancies, more than half experience critical illnesses, and early ICU admission may be the best means of

7

providing them with optimal diagnostic and therapeutic care. I owe an enormous debt of gratitude to the specialists who provided their valuable contributions to this book. Élie Azoulay

 

3

Respiratory Infections in Patients with Hematological Malignancies Ayman O. Soubani

Contents 3.1 Introduction.............................................................

3.1 Introduction 9

3.2 The Immune System Changes in Patients with Hematological Malignancies......................... 10 3.3 Bacterial Pneumonia.............................................. 13 3.4 Fungal Infections.................................................... 17 3.4.1 Aspergillus................................................................ 17 3.4.2 Other Fungi............................................................... 23 3.5 Cytomegalovirus..................................................... 25 3.6 Community Respiratory Viruses........................... 3.6.1 Respiratory Syncytial Virus (RSV).......................... 3.6.2 Parainfluenza Virus................................................... 3.6.3 Influenza................................................................... 3.6.4 Adenovirus................................................................ 3.6.5 Other Viruses............................................................

27 28 29 29 29 29

3.7 Conclusion............................................................... 30 References............................................................................ 30

A.O. Soubani  Associate Professor of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine Wayne State University School of Medicine, Harper University Hospital, 3990 John R-3 Hudson, Deotrit, MI 48201 e-mail: [email protected]

Hematological malignancies are a variety of cancers that involve the hematopoietic cell lines. They include acute and chronic leukemias, Hodgkin’s disease, non-Hodgkin’s lymphomas, multiple myeloma and myelodysplastic syndrome. The age-adjusted incidences of leukemias and lymphomas in the United States are 12.2 and 22.3 per 100,000 population per year, respectively. While the age adjusted death rate for leukemias is 7.3 and for lymphomas is 7.5 per 100,000 population per year [1]. Bone marrow and hematopoietic stem cell transplantations (HSCT) are an important treatment for a variety of hematological malignancies as well as other diseases such as hematological disorders, solid tumors and autoimmune diseases. Annually, there are more than 30,000 cases of autologous HSCT and 15,000 cases of allogeneic HSCT performed worldwide [2]. Hematopoietic stem cells may be obtained from bone marrow, peripheral blood or umbilical cord blood. Depending on the source of these stem cells, HSCT is classified as autologous if the cells are taken from an individual patient and stored for reinfusion after high-dose chemotherapy, and it is classified as allogeneic if the stem cells are donated from another individual (who may or may not be related). In the case of allogeneic HSCT, the conditioning regimen before transplantation may be myeloablative, in which supralethal doses of chemotherapy and irradiation are given, leading to significant toxicity and immunosuppression. More recently, nonmyeloablative regimens have been used to minimize the toxicity related to the conditioning regimen and allow for more robust immunologically mediated killing of tumor cells (graft vs. tumor effect).

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_3, © Springer-Verlag Berlin Heidelberg 2011

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Pulmonary complications, both infectious and noninfectious, are important causes of morbidity and mortality in patients with hematological malignancies (Table  3.1). The incidence of these complications reaches 60% of patients [3, 4]. Mortality of pulmonary complications is 40% and approaches 90% in patients who require mechanical ventilation [5]. The pulmonary complications are generally related to the underlying malignancy or toxicity of the chemotherapeutic regimen. In the case of HSCT, there are additional complications related to graft-vs.-host disease (GVHD), which is a condition in which the donated cells recognize the recipient’s cells as nonself and attack them. Efforts to prevent or treat GVHD include harvesting hemato­ poietic stem cells from an HLA-matched donor and use of immunosuppressive and immunomodulatroy the­ rapy such as corticosteroids, cyclosporine or tacrolimus

Table 3.1  Spectrum of respiratory infectious and noninfectious complications in patients with hematological malignancies Infectious   Bacteria   Mycobacteria   Nocardia   Aspergillus

A.O. Soubani

(FK506) or TNF-a blocking agents [6]. The use of these agents entails further hazards for infectious complications and the development of a new neoplastic disease. The etiology of pulmonary disease following hematological malignancies may be predicted based on variables such as the type of immunodeficiency, the presence of neutropenia, the prophylactic agents the patient is on and the temporal relation to the administration of chemotherapy. The pattern of pulmonary complications is best demonstrated following allogeneic HSCT (Fig. 3.1). This chapter details the spectrum of respiratory infections in patients with hematological malignancy, focusing on HSCT as the prime example of immunosuppression that develops in these patients. The main respiratory infections in patients with hematological malignancies are described along the lines of incidence, risk factors, clinical presentation, and recent advances in the diagnosis and management. The designation of “patients with hematological malignancies” throughout the chapter is used to describe patients who have a malignancy such as leukemia, lymphoma, multiple myeloma or myelodysplastic syndrome; are on chemotherapy; are neutropenic; or underwent HSCT. Data that are unique to one subgroup are specifically mentioned.

  Non-Aspergillus fungi   P. jiroveci   CMV   Community respiratory viruses Non-infectious   Pulmonary edema (cardiogenic and noncardiogenic)   Transfusion-related lung injury   Engraftment syndrome   Diffuse alveolar hemorrhage   Idiopathic pneumonia syndrome   Organizing pneumonia   Drug induced pulmonary toxicity   Radiation pneumonitis   Pulmonary thromboembolic disease   Secondary alveolar proteinosis   Bronchiolitis obliterans   Progression of underlying malignancy

3.2 The Immune System Changes in Patients with Hematological Malignancies The risk of infection in patients with hematological malignancies primarily stems from defects in the number or function of neutrophils, T-cells and B-cells. Abnormalities in each of these cell lines increase the risk of specific infections (Table  3.2). However, the functions of these defense mechanisms are interdependent, so an abnormality in one cell line may compromise the function of other defense mechanisms. Neutropenia is the most frequent immunodeficiency in patients with hematological malignancies. It is seen in patients with acute leukemia and secondary to myelosuppression following chemotherapy. In addition to decreasing the production of neutrophils, cancer chemotherapy and radiation interfere with the chemotactic and phagocytic activity and the intracellular killing

3  Respiratory Infections in Patients with Hematological Malignancies Fig. 3.1  The time line of pulmonary complications following HSCT. HSV herpes simplex virus, HZV herpes zoster virus, CMV cytomegalovirus, RSV respiratory syncytial virus, CHF congestive heart failure, BO bronchiolitis obliterans, VOD veno-occlusive disease, ES engraftment syndrome, DAH diffuse alveolar hemorrhage, BOOP bronchiolitis obliterans organizing pneumonia, IPS idiopathic pneumonia syndrome, PTLPD post transplant lymphoproliferative disorder

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Phase I Pre-engraftment (0–30 days) Host immune system defect

Phase II Phase III Post-engraftment (30– Late Phase 100 days) >100 days)

Neutropenia, mucositis, Impaired cellular immunity catheters and lines, Acute GVHD acute GVHD

Infectioue

Impaired humoral and cellular immunity chronic GVHD

gram - bacteria Gram + bacteria (Staph, Strep)

Encapsulated bacteria

Candida

No cardia

Aspergillus

Aspergillus Pneumocystis HZV

HSV CMV CRV (PIF, RSV, influenza, adenovirus) Non-infectioue

CHF ES

BO

VOD BOOP

DAH IPS

PTLPD

Table 3.2  Spectrum of immunosuppression in patients with hematological malignancies Mechanism of immunosuppression Causes of immunosuppression Spectrum of respiratory infections Neutropenia

Leukemia

Gram-negative bacilli

Myelodysplastic syndrome

Gram-positive cocci

Chemotherapy

Fungi (candida, Aspergillus)

HSCT Neutrophil dysfunction

Lymphoma

Fungi (P. jiroveci, Aspergillus)

Corticosteroids Myelodysplastic Syndrome T-cell defects

Lymphoma

Bacteria (including nocardia, mycobacteria)

Lymphoblastic leukemia Chemotherapy

Viruses (CMV)

Monoclonal antibodies

Fungi (Aspergillus, P. jiroveci)

Corticosteroids

B-cell defects

HSCT

Parasites

Lymphoma

Encapsulated bacteria (S. pneumoniae, H. influenza)

Leukemia Multiple myeloma Splenectomy Monoclonal antibodies Anatomic

Tumor obstruction

Gram-positive cocci

Mucositis

Gram-negative bacilli

Indwelling catheters

Anaerobic bacteria Candida

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of microorganisms by these cells. Furthermore, ­corti­costeroids, used as part of chemotherapeutic regimens, decrease the accumulation of neutrophils at inflammation sites by reducing their adherence and chemotactic properties. The usual infections associated with abnormalities in the number or function of neutrophils are bacteria, including gram-negative bacilli, and opportunistic fungal infections, such as Aspergillus. The risk of infection increases significantly when the absolute neutrophil count falls below 500 cells/mm3. The risk of infection is greatest with neutrophil counts less than 100 cells mm3. The rate of decline in neutrophil count and the duration of neutropenia are also important factors in the risk of infection. Thus, a patient with acute leukemia is at higher risk of infection when the neutrophil count drops rapidly compared to one in whom the counts fall slowly or remain stable. The longer neutropenia lasts, the higher is the risk of infection. Almost all patients with neutrophil counts less than 100 cells mm3 for more than 3 weeks develop fever. Neutropenia that lasts more than 10 days significantly increases the risk of invasive fungal infections. In one study, the risk of Aspergillus infection was increased by 1% each day of neutropenia for the first 3 weeks, then by 4% each day thereafter [7]. B cells differentiate and proliferate to antibody-­ producing plasma cells upon exposure to bacterial antigens. These cells are responsible for the humoral branch of the immune system. They produce different immunoglobulins, such as IgM and IgA, that protect the body against bacteria and viruses. The production of these immunoglobulins is decreased in lymphoproliferative disorders such as chronic lymphocytic leukemia and multiple myeloma, intensive chemotherapy and treatment with monoclonal antibodies such as rituximab. Abnormalities in the B cell number and function predispose to infection with encapsulated bacteria such as Streptococcus pneu­ moniae, Haemophilus influenza and Staphylococcus aureus. T cells are responsible for cellular immunity and play a pivotal role in regulating monocyte-macrophage antigen handling and intracelullar microbial elimination by the release of various cytokines and chemokines. The function of T cells is compromised in patients with malignant lymphomas, especially Hodgkin’s disease, lymphocytic leukemia and T-cell leukemia. Chemotherapeutic agents, such as cyclophosphamide, azathioprime, purine analogues

A.O. Soubani

including fludarabine and cladribine, and imm­ unosuppressive agents inclu­ding corticosteroids, cyclosporine, tacrolimus and sirolimus, suppress the T cell function. Also novel agents used in the management of lypmhoproliferative malignancies, such as monoclonal antibodies anti-CD52 (e.g., alemtuzumab), significantly affect the function of these cells. Abnormalities in T-cell function predispose patients to infections by fungi, including Aspergillus and Pneumocystis jiroveci, viruses, nocardia and mycobacteria. Other factors that compromise the immune system in patients with hematological malignancies and increase the risk of infection include mucositis secondary to chemotherapy that may predispose to aspiration or translocation of microorganisms from the gastro­intestinal tract. Vascular catheters inserted for ­chemotherapy, parenteral nutrition and transfusion of blood products may be a source of bacterial and fungal infections. Splenectomy, which is occasionally performed in the management of patients with mal­ ignant lymphoma, compromises the production of opsonizing antibodies and impairs the defense against encapsulated bacteria. HSCT is the prototype of immunological abnormalities related to hematological malignancies. HSCT recipients develop profound changes in the immune system that affect all lines of defense against infection (Table 3.3). These patients develop neutropenia immediately following transplantation and may have both T- and B-cell problems related to chemotherapy, GVHD and immunosuppressive therapy. The patients typically follow a predictable pattern of immune system deficiency and recovery. During the first month after HSCT, the major host-defense deficits include neutropenia, damaged muc­ocutaneous barriers and indwelling intravenous catheters. The organisms that commonly cause infection during this period include gram-negative bacilli (e.g., Klebsiella, Escherichia and Pseu­domonas), gram-positive cocci (e.g., coagulase-negative and coagulase-positive Staphylococci, Enterococcus), Candida species and herpes simplex virus. Aspergillus spp. may lead to infection if neutropenia persists. During preengraftment, the risks for infection are the same for ­autologous or allogeneic patients, and infection may present as febrile neutropenia. Although fever during this period is probably caused by a bacterial pathogen, an organism or site of infection is infrequently identified. Instead,  such infections are usually treated

3  Respiratory Infections in Patients with Hematological Malignancies Table 3.3  Factors that increase the risk of respiratory infections following HSCT Pre-transplantation   Older age   Pre-transplant immune status   Underlying pulmonary disease   CMV status of the donor and recipient   Residence in endemic areas Transplantation   Allogeneic   Type and intensity of conditioning regimen   Total body irradiation   Delayed engraftment Post-transplantation   Mucositis   Severity and duration of neutropenia   GVHD   T-cell depleting strategies  Nosocomial factors (antibiotic-resistant organisms, indwelling catheters, construction, type of air filtration, transmission of infection by health-care providers)

preemptively or empirically until the neutropenia resolves. Growth factors can be administered to decrease neutropenia duration and complications. The risk of infection persists until the stem cells are engrafted, which is defined as sustained absolute neutrophil count of 500 cells/mm3 and sustained platelet count of >20,000, lasting >3 consecutive days without transfusions. Among unrelated allogeneic recipients, engraftment occurs at a median of 22 days after HSCT (range 6–84 days) [8]. Following engraftment (30–100 days) and in the absence of corticosteroid therapy, neutrophil function is restored, which results in a decreased risk for bacterial and fungal infections. However, all HSCT recipients, and particularly allogeneic recipients, experience an immune system dysfunction for months after engraftment. They may have abnormal CD4/CD8 T-cell ratios, reflecting their decreased CD4 and increased CD8 T-cell counts [6]. They might also have IgG and IgA deficiencies for months after HSCT and have difficulty switching from IgM to IgG production after antigen

13

exposure. Immune system recovery might be delayed further by CMV infection [9]. During this phase, allogeneic HSCT recipients usually develop acute GVHD that manifests as skin, gastrointestinal and liver injury. GVHD is associated with increased risk of infection due to delayed immunologic recovery. Furthermore, the immunosuppressive therapy used for GVHD prophylaxis and therapy puts HSCT recipients at an increased risk for opportunistic viral and fungal infections. The usual infectious agents during this phase include CMV, Aspergillus and P. jiroveci. After 100 days following HSCT, some patients with allogeneic transplantation continue to have manifestations of chronic GVHD. This phase may be associated with cellular and humoral immunodeficiencies, including macrophage deficiency, impaired neutrophil chemotaxis and poor response to vaccination. Also patients may experience long-lasting IgA and IgG deficiencies, poor opsonization and impaired reticuloendothelial function [10, 11]. After chronic GVHD resolves, which might take years, cell-mediated and humoral immunity function are gradually restored. Patients in this phase are at an increased risk for infections caused by encapsulated organisms, such as S. pneumoniae, H. influenzae or Neisseria meningitidis. They may also develop infections as a result of cytomegalovirus (CMV), herpes zoster virus, community respiratory viral infections and Aspergillus.

3.3 Bacterial Pneumonia Bacterial pneumonia caused by gram-positive or gramnegative organisms is a significant problem in patients with hematological malignancies. These bacteria may lead to community- or hospital-acquired pneumonia. They account for 15% of all respiratory infections [12]. Based on surgical lung biopsy, bacterial pneumonia is estimated to be 2%, but increases to more than 25% when documented by autopsy [13]. The mortality associated with bacterial pneumonia in these patients reaches 22% [14]. One of the main challenges in the diagnosis of bacterial pneumonia in patients with hematological malignancies is the inability to identify the organism in the majority of patients, which may underestimate the incidence of these infections. This is related to the contamination of respiratory samples by

14

upper airway organisms, the fact that most of these patients are on prophylactic antibiotics and the limitations in performing invasive procedures such as bronchoscopy to confirm the cause of infection. There is ongoing controversy on the value of these invasive procedures in the diagnosis of bacterial pneumonia in these patients [8]. Factors that generally increase the risk of bacterial pneumonia in patients with hematological malignancies include their immune status, chemotherapeutic regimen, and degree and duration of neutropenia [4, 15]. The presence of GVHD in patients with allogeneic HSCT significantly increases the risk of bacterial pneumonia because of slower reconstitution of the immune system, impairment of the reticuloendothelial system and opsonization. Furthermore, the immunosuppressive therapy to treat GVHD increases the risk of bacterial pneumonia in these patients [15]. Other factors that predispose to bacterial pneumonia include mucositis that increases the risk of aspiration, especially with the use of narcotic analgesics. Indwelling catheters that increase the risk of bacteremia and septic embolization to the lungs (Fig. 3.2) [16]. The presentation of bacterial pneumonia in patients with hematological malignancies may be subtle, and not infrequently patients present with neutropenic fever with no localizing symptoms and signs due to blunted inflammatory response [17]. Radiological signs may also be scarce. The chest radiograph usually shows focal consolidation, however may

Fig. 3.2  CT scan of the chest showing multiple peripheral nodules, some with cavitation, consistent with septic pulmonary emboli in a HSCT recipient with methacillin resistant S aureus bactermia secondary to indwelling central venous catheter

A.O. Soubani

be normal. The infiltrates may progress quickly to multifocal or diffuse changes that are compatible with acute respiratory distress syndrome. High-resolution computerized tomography of the chest is recommended in febrile neutropenic patients, which may show pulmonary infiltrates in up to 50% of patients with negative chest radiographs [18, 19]. A chapter from Heussel in this book details the different CT patterns in hematological patients with pulmonary infiltrates. The main organisms identified as causes of bacterial pneumonia in neutropenic patients and during the pre-engraftment phase of HSCT are usually gram-negative bacteria such as pseudomonas, klebseilla and enterobacter. In a recent report of the utility of bronchoscopy following HSCT, the most commonly isolated bacteria following HSCT was pseudomonas that was resistant to the current antibiotics [8]. There is also increasing incidence of grampositive bacteria, such as S. aureus, Enterococcus faecium and a-hemolytic streptococcus, which may be associated with septic shock and acute respiratory distress syndrome. Anaerobic organisms may be causative agents in the case of aspiration [16, 20, 21]. Following HSCT, patients continue to be at risk for bacterial pneumonia post engraftment of the stem cells, albeit less frequently. The risk factors for bacterial pneumonias during this period are the presence of acute or chronic GVHD and the immunosuppressive therapy used to treat these patients. These patients are at risk of infection with encapsulated organisms such as S. pneumoniae and H. influenza. However, ­gram-negative organisms may be the etiology in up to 25% of patients [12, 14, 15, 22]. In a report of 1,359 HSCT recipients, 25% of the patients developed at least one episode of pneumonia. Bacterial pneumonia was documented in 9% of all patients and was the most common etiology in those in whom an organism was identified. The most frequent isolate was S. pneu­ moniae, and gram-negative organisms were isolated in 23% of those patients. The 1-year survival of patients after bacterial pneumonia was 71% [22]. In another report, S. pneumoniae pneumonia was documented in 0.7% of HSCT recipients. The majority of these patients underwent allogeneic HSCT and had chronic GVHD. Infection was more common in patients with a history of lymphoma and those on high-dose corticosteroid therapy. Pneumococcal vaccine breakthrough developed in 11% of the cases. The infection occurred a mean of 433 ± 669 days post transplan­tation, and 76% of the patients had

3  Respiratory Infections in Patients with Hematological Malignancies

bacteremia. Mortality due to pneumococcal infection was 13%. Admission to the critical care unit and higher APACHE II score were associated with worse outcome [23]. A retrospective report on invasive pseudomonas infection following HSCT revealed the incidence to be 1.65% a median of 63 days post HSCT. Attributable mortality was 36%. The risk factors for poor outcome were the presence of copathogens and highdose corticosteroid therapy. Sixteen percent had recurrence of pseudomonas infection [24]. The clinical and radiological picture is usually classical for bacterial pneumonia. Antibiotic therapy during this period should be based on the organisms suspected or identified. Patients with hematological malignancies are infrequently reported to develop Legionella pneumonia. A recent study of 49 patients found that lymphopenia, the use of systemic corticosteroids and chemotherapy were the most common underlying conditions. Positive DFA was the diagnostic method in 84% of patients. The case fatality rate was 31% [25]. A prolonged course of therapy with macrolide or fluroquinolone may be necessary in the majority of patients. Legionella pneumonia has also been reported following HSCT. Allogeneic HSCT recipients with GVHD seem to be at highest risk for this infection [17, 26]. Empiric broad-spectrum antibiotics should be started immediately when bacterial pneumonia is suspected in patients with hematological malignancies. The American Thoracic Society guidelines for the treatment of health-care associated pneumonia in patients with risk factors such as HSCT or neutropenia recommend a regimen that includes antipseudomonal cephalosporin or carbepenem, or B lactam, plus antipseudomonal fluroquinolone or aminoglycoside, plus linezolid or vancomycin if methicillin-resistant S. aureus is suspected. In patients who develop bacterial pneumonia late following HSCT, coverage of encapsulated organisms with a fluoroquinolone is recommended. The antibiotic regimen should be narrowed if the etiologic agent is identified [27, 28]. The institutional resistance pattern needs to be considered when determining the choice of antibiotics [19]. Further recommendations on the use of anti-bacterial agents in patients with hematological malignancies are provided in the chapter from Legrand et al.

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Prophylactic measures against bacterial pneumonia include intravenous immunoglobulins in allogeneic HSCT recipients with low IgG level (Table 3.4) [29]. Antibiotics with activity against encapsulated organisms are recommended during the treatment of chronic GVHD. However, it should be noted that the routine use of prophylactic fluoroquinolones in the early posttransplant phase may be associated with an increased incidence of infections due to coagulase-negative staphylococci and gram-negative bacilli resistant to fluorquinolones [30]. Nocardia infection has been rarely reported in patients with hematological malignancies with an incidence ranging between 0.3 and 1.7% [31, 32]. In a study of 6,759 HSCT recipients, 22 cases of proven or probable nocardia infection were reported [32]. The infection was diagnosed a median of 210  days following transplantation. The main predisposing factors for developing nocardiosis were neutropenia, active acute or chronic GVHD, and lack of prophylaxis with trimethoprim-sulfamethoxezole (TMPSMZ). In all except one patient, Nocardia asteroides was the causative agent. Pulmonary involvement occurs in 56% of patients, and the most common radiological findings are nodules with or without infiltrates. Cavitary lung lesions and empyema are other common features of nocardia infection (Fig.  3.3). The diagnosis of nocardia pneumonia is usually made by bronchoalveolar lavage (BAL), although occasionally the organism is detected by culture of sputum or tracheal secretions. If these methods are nondiagnostic, then the diagnosis could be confirmed by CT-guided aspirate of a pulmonary nodule or surgical lung biopsy. In 36% of patients there is co-infection with other organisms such as CMV and Aspergillus [32]. Treatment of nocardia infection is by prolonged administration of TMP-SMZ. Second-line agents are available if there are allergy or side effects associated with sulfa preparations. These second-line agents include amikacin, minocycline, cephalosporin or imipenem. Response to treatment is generally good, and long-term survival in patients with nocardiosis is not significantly different from controls [32]. Prophylaxis against P. jiroveci using low-dose TMP-SMZ has an added benefit of reducing the incidence of nocardia infection in high-risk patients. An entire chapter on pulmonary tuberculosis and other mycobacterial infections in patients with

16

A.O. Soubani

Table 3.4  Suggested prophylactic options against respiratory infections in patients with hematological malignancies Infection First choice Alternate choice Comments Bacteria

Fluoroquinolone

Macrolides

Intravenous immunoglobulins only if IgG level <400 mg/dL

9-month therapy Add pyridoxine 25–50 mg daily

Intravenous immunoglobulins Pneumococcal vaccine H. influenza B vaccine Mycobacteria

Isoniazid 300 mg/day

Rifampin

Aspergillus

Posaconazole 200 mg three times daily

Voriconazole Itraconazole Echinocandins

Candida

Fluconazole 400 mg/day orally or IV

Echinocandins

During neutropenia

Voriconazole TMP/SMZ double-strength one tablet/day or three times/week

Dapsone

Prolonged corticosteroids treatment

Aerosolized pentamidine

Allogeneic HSCT: from engraftment for 6 months and during immunosuppressive therapy for GVHD

Gancyclovir 5 mg/kg/dose twice daily for 7–14 days, followed by 5 mg/kg/day for 5 days/week

Foscarnet

Allogeneic HSCT: until day 100 or for a minimum of 3 weeks. Monitor CMV antigen for duration of treatment

RSV

RSV immunoglobulins 750 mg/kg/ month

Aerosolized ribavirin

Influenza

Lifelong annual seasonal Influenza vaccine

Rimantadine

P. jiroveci

CMV

Valgancyclovir

Based on pediatric HSCT during the high season months

Amantadine Oseltamivir

Herpes

Acyclovir 200 mg orally 3 times/ day or 250 mg/m2/dose twice daily intravenously

Valacyclovir

Herpes zoster virus

Herpes zoster immunoglobulin 625 U IM

Acycolvir

hematological malignancies is presented in this book by Dr. Al Anazi and colleagues. Briefly, Myco­ bacterium tuberculosis is rare in patients with hematological malignancies. The incidence of M. tuberculosis in patients with hematological malignancies varies significantly depending on whether the patients lived in an endemic area. In a large cancer center in the United States, the overall rate of active M. tuberculosis infection was 0.2 in 1,000 new cancer diagnoses. Five out of the 18 patients described had hematological malignancies, and 4 were neutropenic [33]. In a report

HSCT: Until engraftment or day 30

Valacycolvir

from India of 130 patients with acute leukemia, 9 cases (6.9%) had active tuberculosis [34]. In HSCT recipients the reported incidence of M tuberculosis ranges from 0.4% to 5.5% [35–40] The prevalence of M. tuberculosis in autologous HSCT is similar to that in the general population, whereas in allogeneic HSCT recipients, M. tuberculosis infection increased by threefold [36]. A recent review of the literature reported the overall frequency of M. tuberculosis infection in HSCT recipients to be 0.4%, with only 2% of infections

3  Respiratory Infections in Patients with Hematological Malignancies

Fig. 3.3  CT scan of the chest showing a wedge shaped infiltrate in the left upper lobe with cavitation in a patient with GVHD on immunosuppressive therapy following HSCT who developed nocardia pneumonia

developing during neutropenia; 23% were during the first 100 days post-transplantation, and 75% were after the first 100  days [40]. In another review of 2,241 patients who underwent HSCT, only 11 patients (0.49%) had mycobacterial infection; 2 patients had M. tuberculosis, 2 M. avium intracellulare and the rest had rapidly growing mycobacteria organisms. All patients responded well to antimycobacterial treatment [35]. The main risk factors for M. tuberculosis in patients with hematological malignancies are allogeneic transplantation, total body irradiation, chronic GVHD, corticosteroid therapy and residence in endemic areas [36–40]. In HSCT recipients the median time for M. tuberculosis infection was 324  days in one study [36]. The clinical and radiological picture of M. tubercu­losis infection in these patients is generally similar to non-immunocom­ promised patients. However, atypical presentations, including rapidly progressive ­disease, lack of cavitation and extrapulmonary manifestations, have been described in patients with hematological malignancies [33, 41]. The diagnosis of M. tuberculosis infection is usually made by smear and culture from sputum, BAL or pleural fluid samples. Rapid diagnosis of M. tuberculosis may be established by PCR test on the above samples. It is important to check the positive samples for drug susceptibility.

17

Treatment of M. tuberculosis infection in patients with hematological malignancies is similar to other patient populations. However, rifampin should be used with caution because of potential interaction with ­commonly used medications in this patient population, such as fluconazole and calcineurin inhibitors [19, 42]. Some studies suggested a full 1 year of treatment [40]. Diagnosis of latent M. tuberculosis may be difficult in patients with hematological malignancies given the degree of immunosuppression. The tuberculin skin test with 5 mm or more induration as well as a history of significant exposure to patients with active M. tubercu­ losis infection may be indications for treatment [19]. Diagnostic yield of T-cell interferon gamma release blood assays is important [43]. Nontuberculous mycobacterial infections (such as M. avium complex, M. kansasii, M. chelonae) are rare in patients with hematological malignancies. In HSCT recipients the incidence has been generally reported to be less than 1% of all patients [44]. However, in one report from Memorial Sloan Kettering Hospital, the incidence of nontuberculous mycobacterial infection was 2.8% of HSCT recipients [45]. This higher incidence was considered to be related to environmental and historical factors. In a review of 93 cases of nontuberculous mycobacterial infection in HSCT recipients reported in the literature, the median time to diagnosis was 4 months following transplantation, and 46% of patients had GVHD. The infection resolved with medical therapy in 62% of patients. The attributed mortality to nontuberculous mycobacteria was 7.5% [44]. Non­tuberculous mycobacteria may colonize the airways of the patients having chronic lung disease, such as bronchiectasis, which may create a challenge in determining the significance of isolating these bacteria from lower respiratory tract samples. In the case of M. avium intracellulare, first-line therapeutic agents include clarithromycin, azithormycin, ethambutol, rifampin and rifabutin for 18 months (12 months after negative cultures) [46, 47].

3.4 Fungal Infections 3.4.1 Aspergillus Aspergillus is a filamentous fungus that is ubiquitous in the environment. The Aspergillus species are present in the environment as small conidia that are

18

regularly inhaled into the lungs. In the lungs, they change into hyphae that are short and septate, with acute angle branching. Alveolar macrophages and peripheral blood neutrophils are the primary defense mechanism against this fungus. T helper cells and their cytokines (such as TNF-a, interferon-g, IL-12 and IL-15) augment the activity of macrophages and neutrophils against Aspergillus. Neutropenia and defects in T-helper cell function in patients with hematological malignancies make these patients especially vulnerable to invasive disease by Aspergillus. A chapter from Bougnoux and colleagues in this book reports an upto-date and comprehensive review on invasive pulmonary aspergillosis in patients with hematological malignancies. Invasive pulmonary aspergillosis (IPA) is the most common invasive fungal infection in patients with hematological malignancies, with a steady rise in the documented cases. Following HSCT, the risk for IPA is much higher following allogeneic HSCT when compared to autologous transplantation (incidence is 0.5–4% in autologous HSCT compared to 2.3–15% in allogeneic HSCT [48–52]). After autologous HSCT, IPA is mainly seen during the neutropenic phase. In allogeneic HSCT, the highest risk is in patients with severe GVHD (grade III-IV). In a study by Marr et al., the probability of IPA following allogeneic HSCT reached approximately 5% at 2  months, 9% at 6 months and 10% at 1 year following allogeneic HSCT. By the third year after transplantation, the probability of IPA increased minimally to 11.1% [50]. In these patients, the timeline for IPA infection follows a bimodal distribution, with a peak in the first month following HSCT, which is associated with neutropenia. The second peak is during the treatment for GVHD (median 78–112  days post transplantation) [49, 51, 53]. The first peak is currently less significant due to the routine use of stem cell instead of bone marrow for transplantation, non-myeloablative regimens, the use of colony-stimulating factors during neutropenia and the widespread use of antifungal agents have significantly decreased the incidence of IPA during this period [49, 54]. On the other hand, the incidence of IPA during the treatment of GVHD has become more significant, especially with higher incidence of GVHD associated with unrelated allogeneic transplantation and nonmyeloablative HSCT. Cord blood HSCT is also associated with increased risk of IPA. In one study of patients who received low intensity cord blood transplantation, the 3-year accumulative incidence of IPA

A.O. Soubani

was 10% with mortality of 86%. All of these patients developed IPA in the first 100 days post transplantation (median 20 days) [55]. Also the risk of IPA increases with the use of Alemtuzumab, which is an anti-DC52 monoclonal antibody used to deplete peripheral B and T lymphocytes [49, 50, 52]. Treatment of GVHD with intensive immunosuppressive therapy, including corticosteroids, cyclosporine A and anti-TNF- a agents, further increases the risk of IPA [49, 50, 56–58]. There is also evidence that CMV infection in these patients increases the risk of IPA [50, 59]. The hazards ratio for IPA in the setting of CMV disease increases by 13.3 folds (95% CI 4.7–37.7) [51]. A recent retrospective review of 385 cases of suspected or documented IPA in patients with hematological malignancies over a 9-year period revealed that the overall and disease-specific survival rates were 52% and 60%, respectively. Factors that predicted mortality were allogeneic HSCT, neutropenia, progression of the underlying malignancy, prior respiratory disease, corticosteroids therapy, renal impairment, low monocyte counts, disseminated aspergillosis and pleural effusion [60]. Aspergillus is most often introduced to the lower respiratory tract by inhalation of the infectious spores. Less commonly, IPA may start in locations other than the lungs, like sinuses, the gastrointestinal tract, or the skin (intravenous catheters or prolonged skin contact with adhesive tapes) [61–64]. Patients present with symptoms that are usually non-specific and consistent with bronchopneumonia, with fever unresponsive to antibiotics, cough, sputum production and dyspnea. Patients may also present with pleuritic chest pain (due to vascular invasion leading to small pulmonary infarcts) and hemoptysis, which is usually mild, but could be massive. IPA is one of the most common causes of hemoptysis in neutropenic patients and has been reported to be associated with cavitation that occurs with neutrophil recovery [65]. Aspergillus infection may also disseminate hematogenously to other organs, most commonly the brain (leading to seizures, ringenhancing lesions, cerebral infarctions, intracranial hemorrhage, meningitis and epidural abscess), and less frequently other organs such as skin, kidneys, pleura, heart, esophagus and liver may be involved [66]. The diagnosis of IPA is challenging. Early diagnosis of IPA in patients with hematological malignancies remains difficult, and a high index of suspicion is necessary in patients with risk factors for invasive disease. Histopathological diagnosis by examining lung tissue

3  Respiratory Infections in Patients with Hematological Malignancies

19

obtained by surgical lung biopsy remains the “gold standard” for the diagnosis of IPA [67]. The presence of septate, acute, branching hyphae invading the lung tissue samples along with a culture that is positive for Aspergillus species from the same site is diagnostic of IPA. Histopathological examination also allows for the exclusion of other diagnoses, such as malignancy or nonfungal infectious diseases. The histopathological findings associated with IPA have been recently shown to differ according to the underlying host. In patients with allogeneic HSCT and GVHD, there is intense inflammation with neutrophilic infiltration, minimal coagulation necrosis and low fungal burden. On the other hand, IPA in neutropenic patients is characterized by scant inflammation, extensive coagulation necrosis associated with hyphal angioinvasion and high fungal burden. Dissemination to other organs is equally high in both groups [68]. The chest radiograph has a small role in early stages of the disease because the incidence of non-specific changes is high. Usual findings include rounded densities, pleural-based infiltrates that are suggestive of pulmonary infarctions and cavitations. Pleural effusions are uncommon [69, 70]. Chest CT scan, especially when combined with high-resolution images, is a much more helpful tool in the diagnosis of IPA. The routine use of high-resolution CT of the chest early in the course of IPA has been shown to lead to earlier diagnosis and improved outcome of these patients [71, 72]. It also aids further diagnostic studies such as bronchoscopy and surgical lung biopsy [73]. The typical chest CT scan

findings in patients suspected to have IPA include: multiple nodules and the halo sign, which is mainly seen in neutropenic patients early in the course of infection (usually in the first week), and appears as a zone of low attenuation due to hemorrhage surrounding the pulmonary nodule (Fig. 3.4). Another late radiological sign is the air crescent sign, which represents crescent-shaped lucency in the region of the original nodule secondary to necrosis [70, 74]. Neither the halo nor the air crescent signs are sensitive to or pathognomic of IPA. The halo sign may be found as a result of metastasis, organizing pneumonia or other fungal infection [75]. Greene et al. found that 94% of 235 patients with a confirmed diagnosis of IPA had at least one nodular region [76]. In another recent report of 27 patients with IPA following allogeneic HSCT, the most common radiological findings were ill-defined consolidation (48%), nodules with halo sign (44%), centrilobular nodules (44%), groundglass-attenuation (22%) and pleural effusion (26%) [77]. In a large study of 236 patients with IPA, 86% of whom had hematological malignancies, the halo sign was detected in 61% of the cases. In the study population as a whole, and specifically in patients with hematological malignancies, the presence of the halo sign predicted better response to antifungal therapy [78]. On the other hand, in a retrospective study done on 45 patients, Horger et al. found that none of the early highresolution CT scan signs (nodule, consolidation, peribronchial infiltrates) seems to predict patient outcome or the development of pulmonary hemorrhage [79]. However, pulmonary hemorrhage is expected to occur

Fig. 3.4  (a) High resolution CT scan of the chest showing right upper lobe nodule with the Halo sign in a patient with nonHodgkin’s lymphoma and neutropenia who developed IPA.

(b) Shows residual cavity formation after 2 months of treatment with antifungal agent

20

in the presence of large cavitating nodules or consolidations located close to larger pulmonary vessels. The significance of isolating Aspergillus species in sputum samples depends on the immune status of the host. In patients with hematological malignancies, isolation of Aspergillus species from sputum is highly predictive of invasive disease. Studies have shown that sputum samples that are positive for Aspergillus in these patients have a positive predictive value of 80–90% [80–82]. However, sputum samples that are negative could not rule out IPA, since negative sputum studies have been noted in 70% of patients with confirmed IPA [82, 83]. Blood cultures are rarely positive in patients with confirmed IPA [84]. Bronchoscopy with BAL is generally helpful in the diagnosis of IPA, especially in patients with diffuse lung involvement. Visualization of the bronchial tree may also provide arguments for IPA in patients with airway-invasive IPA. The sensitivity and specificity of a positive result of BAL fluid are around 50% and 97%, respectively. The yield of BAL in the diagnosis of IPA is not consistent, and there are reports of much lower diagnostic yield [80, 81, 85–89]. BAL is generally a safe and useful tool in non-hypoxemic patients with hematological malignancies suspected to have IPA. In addition to obtaining samples for fungal stain and culture, it may be useful in detecting Aspergillus antigens in the BAL fluid and excluding other infections. Transbronchial biopsies usually do not add much to the diagnosis of IPA and are associated with increased risk of bleeding, so they are usually not performed [80]. In the setting of diagnostic workup for IPA, it is important to send samples such as sputum, BAL fluid or lung tissue for culture as well as for histological examination. This is because other fungal species, such as scedosporium, pseudallescheria and fusarium, may have a similar histological appearance as Aspergillus [90]. Furthermore, there are different species of Aspergillus that may lead to IPA. While Aspergillus fumigatus is the most common cause of IPA, there are increasing reports of IPA in patients with hematological malignancies due to other species such as A. niger, A. terreus and A. flavus [91–95]. Some of these species (such as A. terreus and A. nidulans) are resistant to amphotericin B [92, 95]. In a review of 300 patients with hematological malignancies (40% were HSCT recipients) with proven IPA, A. terreus was the second most common species isolated with a frequency of 23%. The risk factors and outcome for A. terreus infection were similar to those for A. fumigatus infection;

A.O. Soubani

however the former was significantly more likely to be nosocomial in origin and more likely to be resistant to amphotericin B [94]. The new triazole antifungal agents such as voriconazole and posaconazole have significantly better efficacy against A. terreus [92, 93, 96]. The most recent advances in the diagnosis of IPA are related to detecting Aspergillus antigens in body fluids. Galactomannan (GM) is a polysaccharide cellwall component that is released by Aspergillus during growth. A double-sandwich ELISA for the detection of GM in serum was approved by the Food and Drug Administration for the diagnosis of IPA, with a threshold of 0.5 ng/mL. It is reported that serum GM can be detected several days before the presence of clinical signs, an abnormal chest radiograph or positive culture. Thus, GM detection may allow earlier confirmation of the diagnosis, and serial determination of serum GM values may be useful in assessing the evolution of infection during treatment [97, 98]. A meta-analysis study was undertaken by Pfeiffer et al. to assess the accuracy of a GM assay in diagnosing IPA. Twenty-seven studies from 1996 to 2005 were included, and cases were diagnosed to have IPA according to the European Organization for Research on Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria. Overall, the GM assay had a sensitivity of 71% and specificity of 89% for proven cases of invasive aspergillosis. The negative predictive value was 92–98%, and the positive predictive value was between 25% and 62% [99]. Pfeiffer and colleagues concluded that GM assay is more useful in patients who have hematological malignancies or who have undergone allogeneic HSCT than in solid-organ transplant recipients or nonneutropenic patients. GM is found in food and may be absorbed by the digestive tract, especially in patients with postchemotherapy mucositis, resulting in a false-positive reaction. Also medications such as b-lactam antibiotics (e.g., piperacillin/tazobactam) may be associated with false-positive GM assay, while antifungal agents with activity against Aspergillus may lead to a false-negative test [100–103]. It is noteworthy that GM assay is species specific, and it is not possible to exclude the involvement of other molds such as Fusarium, Zygomycetes and dematiaceous fungi by measuring serum GM [104]. There is evidence that GM is detected in other body fluids such as BAL, urine and cerebrospinal fluid, and that these tests may become positive prior to clinical and radiological findings suggestive of IPA [104–107].

3  Respiratory Infections in Patients with Hematological Malignancies

A recent prospective study of 200 patients with hematological malignancies and profound neutropenia found that GM assay from BAL had a sensitivity of 100% for IPA compared to 71% by serum GM assay [108]. Another study done by Musher et  al. showed that incorporating GM assay and quantitative PCR assay into standard BAL fluid analysis may enhance bronchoscopic identification of Aspergillus species as the cause pulmonary disease in patients with hematological malignancies [105]. Serial serum GM assay has also been shown to help in the early detection of IPA and as a surrogate to response to therapy. In a study of 70 neutropenic patients with IPA, serum GM assay was performed three times weekly after the start of antifungal therapy until GM index negativity or death. The patients who had normalization of the serum GM index did significantly better than those who continued to have positive serum GM [109]. Polymerase chain reaction (PCR) is another way to diagnose IPA by the detection of Aspergillus DNA in BAL fluid and serum. A positive Aspergillus PCR in BAL fluid has an estimated sensitivity of 67–100% and specificity between 55% and 95% [110]. PCR sensitivity and specificity have also been reported as 100% and 65–92%, respectively, in serum samples [110–113]. However, this test is often associated with false-positive results because it doesn’t discriminate between colonization and infection. PCR for Aspergillus nucleic acid detection remains restricted to highly specialized laboratories and cannot be considered as a routine exam. Detection of serum (1 → 3)-b-d-glucan, a fungal cell wall constituent, has recently received Food and Drug Administration approval. Determination of plasma (1 → 3)-b-d-glucan has been reported to be a highly sensitive and specific test for invasive deep mycosis, including candidiasis, fusariosis, Pneumo­cystosis and aspergillosis, and could be useful in the immunocompromised patients [114]. A prospective study of 95 patients with hematological malignancies and neutropenia evaluated the value of monitoring the serum level of (1 → 3)-b-d-glucan twice weekly in the absence of fever and daily in the presence of fever in the early diagnosis of IPA. Thirteen patients developed IPA, 15 patients had candidiasis, and 2 patients had mixed invasive fungal infections. The sensitivity, specificity, positive predictive value and negative predictive value of two consecutive positive (1 → 3)-b-d-glucan values were 0.63, 0.96, 0.79 and 0.91, respectively [115]. The utility of routine monitoring of this assay in patients with hematological malignancies at high risk for IPA is not yet defined.

21

The role of GM and other serological studies in the diagnosis of IPA is evolving. Furthermore, their role in different hosts, as surveillance tools, and their impact on the outcome of patients are not clear. There are ongoing prospective studies to address these issues. Until solid data are available, these tests should be considered as adjunct diagnostic studies, and should not replace appropriate clinical and radiological evaluation, and in selected cases, invasive procedures to confirm the diagnosis of IPA. The EORTC/MSG has revised its criteria for the diagnosis of invasive fungal infections [116, 117]. These criteria consist of host factors, microbiologic, minor and major clinical criteria (Table 3.5). Positive serum GM, with the appropriate host and clinical Table 3.5  The diagnostic criteria for IPA Diagnosis Criteria Proven IPA

Histopathologic or cytopathologic examination of lung tissue showing hyphae from needle aspiration or biopsy specimen with evidence of associated tissue damage; OR Positive culture result for Aspergillus from a sample obtained by sterile procedure from the lung and clinically or radiologically abnormal site consistent with infection

Probable IPA

Host risk factora; AND Microbiological criteria (positive Aspergillus microscopy or culture from the sputum or BAL, or positive GM assay); AND Clinical criteria consistent with the infection (1 major or 2 minor)b

Possible IPA

Host risk factor; AND Microbiological criteria (positive Aspergillus microscopy or culture from the sputum or BAL, or positive GM assay from one BAL or at least two serum samples); OR Clinical criteria consistent with the infection (1 major or 2 minor)a

At least one of the following host factors include neutropenia (<500 cells/mm3 for >10  days), allogeneic HSCT, prolonged corticosteroid therapy (>0.3 mg/kg/day of prednisone or equivalent for >3 weeks); T cell suppressant therapy b Major clinical criteria are: new characteristic infiltrates on CT imaging (halo sign, air-crescent sign, or cavity within area of consolidation). Minor clinical criteria are: Symptoms of LRTI (cough, chest pain, hemoptysis, or dyspnea); physical finding of pleural rub; any new infiltrate not fulfilling major criterion; pleural effusion a

22

factors, can be considered as “probable” IPA. The EORTC/MSG criteria are not evidence-based and are not prospectively validated. Instead, they are meant to serve as a guide for clinical and epidemiological research and need not be present in every patient to treat for IPA. The treatment of IPA is difficult, and the mortality rate is still high despite the introduction of several new antifungal agents. Herbrecht and colleagues report in this book a very comprehensive and up-to-date contribution on antifungal agents. Therapy should be considered as soon as there is a clinical suspicion of IPA and while a workup is underway. For many years, amphotericin B has been the first line of therapy for IPA. The recommended dose is 1–1.5 mg/kg/day. Amphotericin B is known, however, to cause serious side effects, including nephrotoxicity, electrolyte disturbances and hypersensitivity. For these reasons, this agent nowadays has little role to play in the treatment of IPA, and newer lipid-based preparations of amphotericin B (e.g., liposomal amphotericin B and lipid complex amphotericin B) have been introduced to minimize these side effects. Higher doses of the lipid formulations are needed for equivalent antifungal efficacy to amphotericin B. Voriconazole is a new broad-spectrum triazole that is approved as the initial treatment of invasive aspergillosis and is currently considered the treatment of choice in many patients with IPA [118–120]. In a large prospective, randomized, multicenter trial, voriconazole was compared to amphotericin B as the primary therapy for IPA [121]. Patients receiving voriconazole had a higher favorable response rate at week 12 (53% compared with 32% in patients receiving amphotericin B) and a higher 12-week survival (71% compared with 58%). Voriconazole is available in both intravenous and oral formulations. The recommended dose is 6 mg/kg twice daily intravenously on day 1 followed by 4  mg/kg/day. After 7  days, switching to 200  mg orally twice daily may be considered. Voriconazole has a milder side effect profile and is much better tolerated than amphotericin B. The most frequent adverse effect is visual disturbances described as blurred vision, photophobia and altered color perception. Liver function test abnormalities and skin reactions are less common side effects associated with voriconazole treatment. It is important to note that voriconazole is associated with a significant number of drug-drug interactions such as cyclosporine, warfarin, terfenadine, carbamazepine, quinidine, rifampin, statins and sulfonylureas [118].

A.O. Soubani

Posaconazole is another broad-spectrum triazole that has been shown to be effective and safe as salvage therapy in patients with invasive aspergillosis refractory to standard antifungal therapy [96, 122, 123]. Echinocandin derivatives such as caspofungin, micafungin and anidulafungin are effective agents in the treatment of IPA refractory to standard treatment or if the patient could not tolerate first line agents [124, 125]. In its recent guidelines, The Infectious Disease Society of America recommends voriconazole as the primary treatment for IPA in most patients and liposomal amphotericin B as an alternative treatment for some patients. For salvage therapy, agents include lipid-based preparations of amphotericin A, posaconazole, itraconazole, caspofungin or micafungin [126]. Some studies have suggested that combination antifungal therapy could be a strategy to treat refractory IPA [127, 128]. There are no prospective randomized studies that show superior efficacy of combination therapy over a single agent in the primary management of IPA. There are in  vitro and limited clinical studies in the form of case reports and retrospective case series that show a benefit from combining antifungal agents as salvage therapy in refractory IPA [128–131]. The combination of caspofungin and liposomal amphotericin B as a salvage therapy showed an overall response rate of 42%; however, in patients with progressive documented IPA, the response rate was only 18% [128]. A survival advantage of voriconazole plus caspofungin compared with voriconazole alone was reported by Marr et al. in a retrospective analysis of salvage therapy for IPA [130]. On the other hand, the report by Denning et al. showed no difference in the response rate between patients who received micafungin alone or in combination with other antifungal agents as primary or salvage therapy for IPA [132]. Combination therapy of an echinocandin with either a lipid formulation of amphotericin B or triazole agent appears to be promising, however cannot be recommended for the routine treatment of primary IPA. Controlled randomized prospective studies are needed to document the value of this approach. Surgical resection has a limited role in the management of patients with IPA; however, it should be considered in cases of massive hemoptysis or pulmonary lesions close to the great blood vessels or pericardium, or the resection of residual localized pulmonary lesions in patients with continuing immunosuppression. Several reports have shown the relative efficacy and safety of surgical intervention – in

3  Respiratory Infections in Patients with Hematological Malignancies

addition to antifungal therapy – in these situations [72, 133–138]. Immunomodulatory therapy, such as using colonystimulating factors (i.e., granulocyte-colony stimulating factors, granulocyte macrophage-colony stimulating therapy) or interferon-g, could be used to decrease the degree of immunosuppression and as an adjunct to antifungal therapy for the treatment of IPA. Colonystimulating factors stimulate the bone marrow to produce more neutrophils and have been shown to augment the phagocytic activity of neutrophils against fungi, including Aspergillus species [139–141]. There is a theoretical advantage to adding these agents to the treatment of neutropenic patients suspected to have IPA. In one randomized study in patients receiving chemotherapy for acute myelogenous leukemia, prophylaxis with GM-CSF led to a lower frequency of fatal fungal infections compared with placebo (1.9% vs. 19%, respectively) and reduced overall mortality [142]. It is recommended to consider colony-stimulating factors in neutropenic patients with serious infections; however, there are no definitive studies that show benefit in patients with IPA [143]. Interferon-g is another cytokine that has been shown in vitro and in animal models to augment immunity by increasing neutrophil and monocyte activity against Aspergillus [140, 144, 145]. The value of adding interferon-g as an adjunct treatment of IPA is limited to case reports and small reports, and there are no guidelines on its role in the treatment of IPA [146]. There was a concern about the use of interferon-g in allogeneic HSCT recipients, since it may worsen GVHD; however, a recent trial showed that GVHD may actually improve during this therapy [147]. Granulocyte transfusion is another potential supportive therapy for patients with prolonged neutropenia and life-threatening infections refractory to conventional therapy. It has been shown that it is safe for potential donors to donate neutrophils by granulocytophoresis; however, there are no randomized studies that prove the benefit of adjuvant granulocyte transfusion in the treatment of IPA [148]. A review of 66 observational studies of patients who received ganulocyte transfusions, either prophylactic or therapeutic, in the management of gram-negative bacterial or fungal infections suggested survival in 70% [149]. It is also important in patients with IPA, whenever possible, to decrease the dose of systemic corticosteroids and immunosuppressive agents. The management of IPA is difficult and an important approach to this problem is prophylaxis for those patients

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who are at increased risk for this infection. Avoiding the hospitalization of patients in areas where there are construction and the use of high-efficiency particulate air (HEPA) filtration with or without laminar air flow ventilation have proven to be efficient [150]. A meta-analysis suggested that itraconazole was effective in preventing fungal infections in neutropenic patients [151]. Recent data also suggest the efficacy of posaconazole in the prophylaxis against IPA in patients with severe GVHD and other hematological malignancies [152, 153]. There are also preliminary data that suggest aerosolized treatment with antifungal agents such as liposomal amphotericin B and voriconzaole may be effective in the prevention of IPA in high risk population [154, 155].

3.4.2 Other Fungi Other fungal infections may invade the lungs in hematological patients. An entire chapter on emerging fungal infections from Drs. Garnica and Nucci is provided in this book. These invasive fungal infections primarily involve the lungs, but may disseminate to other organs. They are mainly seen in patients with neutropenia, allogeneic HSCT, and GVHD [52, 156–159]. The main invasive fungal infections that are reported in these patients include hyaline hyphomycetes (such as fusarium and Scedosporium), zygomycetes and endemic fungi. In a Centers for Disease Controlsponsored surveillance program for invasive fungal infections, there were 886 patients with invasive fungal infections out of 20,000 HSCT and solid organ transplant recipients [160]. Non-apsergillus molds were responsible for 14% of infections, cryptococcus in 4%, endemic fungi in 3% and pneumoystis in 2%. Hyaline hyphomycetes, such as fusarium and scedosporium, are the main non-aspergillus molds that are reported in patients with hematological malignancies. These organisms resemble Aspergillus histolo­gically with septate hyphae that invade blood vessels [52, 161, 162]. Culture is the only means to distinguish these organisms from Aspergillus. The lungs are the primary site of infection; however, these organisms have the tendency to disseminate. In one study, fusarium infection involved the lungs in 81% of the cases, and was disseminated in 74% of the patients [52]. Fungemia due to fusarium is reported in 20–70% of patients [163]. These infections usually occur early (in the first 2 months) following allogeneic HSCT. The mortality

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in patients with pulmonary fusariosis is 65% within 1 month of diagnosis [164]. Factors that decrease survival are persistent neutropenia and corticosteroid therapy. Scedosporium has been isolated from the air in hospitals [162]. In the lungs, these organisms usually present with thin wall cavities or nodules with or without air-crescent sign that are refractory to antibiotics and antifungal therapy [165]. The diagnosis is usually confirmed by isolating the organisms by culture of BAL fluid or lung tissue obtained by surgical lung biopsy. Occasionally the diagnosis is obtained by fungal blood cultures. Mortality associated with these fungal infections remains very high, in the range of 70–100% [163, 166–168]. Zygomycetes such as Rhizopus and mucor are characterized by sparsely septate, broad hyphae with irregular branching. They have the tendency to invade blood vessels with thrombosis and tissue necrosis. They usually involve the sinopulmonary tree; however dissemination to other organs is rare. The incidence of zygomycetes infections in patients with hematological malignancies is rare (0.5–1.9%) [52, 158, 159]. It is important to note that these organisms may be resistant to voriconazole [169]. Recent reports suggest good response to posaconazole [170]. Mortality associated with zygomycetes infection in patients with hematological malignancies reaches 80% [52, 158, 159]. Cryptococcus infection in patients with hematological malignancies has been rarely reported. The widespread prophylaxis with fluconazole may account for the relatively low incidence in these patients. Patients with profound T cell depression (such as Hodgkin’s disease, chronic leukemia and treatment with purine analogues) are at highest risk [171]. The diagnosis of pulmonary cryptococcal infection is usually made by detection of the fungus in BAL or lung tissue samples. Serum cryptococcal antigen has more than 95% sensitivity and specificity in the diagnosis of invasive cryptococcosis, however could be negative in patients with localized pulmonary infection [172]. The treatment of pulmonary cryptococcosis in hematological malignancies includes Amphotericin B for severe cases, and fluconazole or itraconazole for milder cases and for maintenance therapy [173]. As reported in the chapter from Carvajal et al., invasive Candida infection develops in 11–16% of patients with hematological malignancies, and pulmonary involvement is usually secondary to disseminated

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candidiasis or candidemia. Autopsy studies suggest that 50% of infected patients have pulmonary involvement [174]. In a study of 529 patients who died from leukemia or myelodysplastic syndrome and were affected by candidiasis, 45% had lung involvement. It is believed that Candida may have disseminated to all organs, including the lungs, prior to their death [175]. Primary Candida pneumonia is extremely rare. Histopathological confirmation is necessary in most of the cases. The universal prophylaxis with fluconazole has significantly decreased the incidence of Candida infections. However, there is a shift in the Candida species from Candida albicans to more resistant species such as C. glabrata or C. krusei. As reported in the dedicated chapter, Pneumocystis pneumonia is caused by P. jiroveci, which is a fungal agent [176]. Infection is caused by inhalation of aerosolized organisms. The incidence of P. pneumonia was historically up to 20% of patients with hematological malignancies and 5–15% of HSCT recipients [4, 177]. However, the routine prophylaxis with TMX/ SMZ during high-risk periods has significantly decreased the incidence of this infection to negligible values. Breakthrough infection in patients on TMP/ SMZ prophylaxis is extremely rare, however is possible in patients on other prophylactic agents such as low-dose atovaquone or aerosolized pentamidine [178–180]. Patients with lymphoproliferative disorders appear to be at the highest risk for P. jiroveci infection. Also the prolonged administration of high-

Fig. 3.5  High resolution CT scan of the chest showing diffuse ground glass infiltrates in a patient with non-Hodgkin’s lymphoma on chemotherapy who developed P jiroveci pneumonia

3  Respiratory Infections in Patients with Hematological Malignancies

dose corticosteroid therapy and purine analogues such as fludarabine–especially when combined with corticosteroids–significantly increase the risk of this infection [181–184]. In a recent report of 519 allogeneic HSCT recipients, P. jiroveci pneumonia was documented in 13 patients (2.5%). The majority of cases occurred late in the course following HSCT (median 14.5  months) after discontinuation of prophylactic agents [185]. The CD4+ T cell count was low, and 70% of patients were on immunosuppressive therapy for chronic GVHD. The onset of P. jiroveci pneumonia is acute and rapidly progressive in the majority of cases, with dyspnea, nonproductive cough and fever. Hypoxemia is usually dramatic in these patients [183]. Radiologically, there are perihilar interstitial or alveolar infiltrates. Groundglass opacities may be the prominent finding on highresolution CT scan of the chest (Fig. 3.5). LDH may be elevated. The diagnosis is usually made by bronchoscopy with BAL; however, the sensitivity of this procedure is lower than that reported in patients with AIDS due to the lower burden of the organism [4]. Monoclonal antibodies for detecting P. jiroveci have higher sensitivity and specificity in induced sputum samples than conventional staining, but the difference between the two methods is insignificant in BAL fluid [186, 187]. Mortality has been recently reported to be 20% of patients with cancer, and the only predictor of poor outcome based on multivariate analysis was the need for mechanical ventilation [188, 189]. Prophylaxis against P. jiroveci pneumonia using TMP/SMZ is recommended for patients who are on chronic corticosteroid therapy and following engraftment in allogeneic HSCT recipients for 120 days. However, if the patient has chronic GVHD, prophylactic treatment is recommended as long as they are on immunosuppressive therapy for this condition. Endemic mycoses, such as histoplasmosis, blastomycosis and coccidiomycosis, are rare in patients with hematological malignancies [190]. These infections tend to have geographical distribution and are usually caused by endogenous reactivation of a latent infection. The infection usually presents with progressive pulmonary disease that disseminates to other organs. Treatment is with a high-dose amphotericin B preparation [161]. After controlling the infection, an azole such as itraconazole (or fluconazole in the case of coccidiomycosis) can be used as a maintenance treatment [160].

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3.5 Cytomegalovirus It is important at the outset to define the different manifestations of CMV infection. CMV infection is defined as isolation of the CMV virus or its proteins or nucleic acid from body fluids or tissue specimens. CMV viremia is isolation of CMV from blood by culture. CMV antigenemia is detection of CMV pp65 in circulating leukocytes or CMV DNA by PCR techniques. CMV disease is the presence of signs and symptoms related to CMV infection, and may manifest as hepatitis, ­gastroenteritis, encephalitis or a systemic syndrome. CMV pneumonia is one of the most frequent and severe manifestations of CMV disease in patients with hematological malignancies, especially HSCT recipients. It is defined as pulmonary signs and symptoms combined with detection of CMV in pulmonary samples (BAL or lung tissue). It is important to note that some patients may shed CMV in BAL fluid in the absence of invasive disease. It is also significant to note that CMV affects the immune system and promotes other infections. Co-infection with other organisms, such as bacteria, P. jiroveci, Aspergillus or other viruses, is reported in up to one third of cases [191]. An entire very nice contribution from Dr. Vigil and Chemaly in this book provides a comprehensive ­overview on CMV pneumonia. Traditionally, CMV pneumonia was a relatively frequent infection in patients with hematological malignancies. It was diagnosed in 20–35% of allogeneic HSCT recipients and 60–80% of patients with diffuse pneumonitis following HSCT [29, 192, 193]. CMV pneumonia usually presented in the first 2  months post-transplantation (median 44 days), and was associated with high mortality ranging between 80% and 100% [192]. However, antiviral prophylaxis for high-risk patients and preemptive therapy has changed the epidemiology of CMV pneumonia in HSCT recipients. Currently in allogeneic HSCT recipients, the incidence of CMV pneumonia is about 10%, while in autologous recipients, CMV pneumonia is extremely rare (1–9%) [194– 197]. An autopsy-based case control study evaluated the incidence and risk factors of fatal CMV pneumonia in patients with hematological malignancies. The incidence of fatal CMV pneumonia was 3.5% before 1997 compared to 0.8% after that date. Complete remission of the underlying malignancy and sustained lymphopenia were independent predictors of CMV pneumonia [198]. Prophylactic and preemptive antiviral therapy

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has also shifted the onset of CMV pneumonia in allogeneic HSCT to after the first 100  days (median 169 days), especially in patients with non-myeloablative HSCT and during the treatment of chronic GVHD [199, 200]. The risk of CMV pneumonia in patients with hematological malignancies is mainly seen in patients with leukemia or lymphoma who are on T-cell-depleting chemotherapeutic regimen (such as ­cytarabine, fludarabine, high-dose cyclophosphamide, corticosteroids or alemtuzumab). In HSCT recipients, CMV pneumonia is mainly seen after allogeneic transplantation and the highest risk is in seropositive recipients. CMV disease is reported in 14% of seropostive recipients who received a seropositive graft and in 12% of seropositive recipients and seronegative grafts. On the other hand, the risk of CMV disease is lower in seronegative recipients who had HSCT from seropositive donors (incidence is less than 5%) [201]. Additional risk factors for CMV pneumonia include older age, total body irradiation, myeloablative chemotherapy, the presence and acuity of acute GVHD, and the use of T-cell depletion strategies [192, 202, 203]. In autologous HSCT, the main risk factors for CMV pneumonia are the presence of CMV infection prior to transplantation, CD-34-enriched stem cells, probably due to lower number of T cells and delayed immunologic reconstitution [204]. CMV pneumonia presents clinically with rapid onset of fever, nonproductive cough, dyspnea and hypoxemia. Pleurisy may be present. The respiratory symptoms usually progress to acute respiratory failure within 2 weeks. Radiologically, the most common findings are an interstitial pattern with tiny pulmonary nodules and patchy areas of consolidation. Rarely CMV pneumonia may present with focal diseases [205, 206]. High-resolution CT scan of the chest is more sensitive in detecting the findings related to CMV pneumonia including diffuse or patchy groundglass opacification, thickened interlobular septa and tree in bud nodular changes. Pleural effusion may be present in around quarter of patients [206]. The differential diagnosis of these clinical and radiological findings includes P. jiroveci, other viral infections, pulmonary hemorrhage, drug-induced lung injury, pulmonary edema or tumor recurrence. Some of these conditions may co-exist with CMV pneumonia. The hallmark of the histopathological findings of CMV pneumonia is demonstrating the intracytoplasmic inclusion bodies within areas of inflammation on lung

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biopsy. These eosinophilic bodies may be absent early in the process. There are also areas of mononuclear interstitial pneumonitis with or without alveolar epithelial desquamation and hyaline membrane formation. These findings can be rarely demonstrated by bronchoscopic biopsy; however, usually surgical lung biopsy by video-assisted thoracoscopy is necessary. Cytological examination of the BAL fluid to detect the inclusion bodies within the lower respiratory tract epithelial cells is highly specific (98%) for CMV pneumonia, but has low sensitivity, with a positivepredicted value of 73% and a negative predictive value of 99.5% [207]. On the other hand, rapid culture of the BAL fluid using the shell viral technique is highly sensitive (99%) in detecting the virus, but lacks the specificity (67–83%), since it cannot differentiate between viral shedding and invasive disease [207, 208]. The value of detecting CMV antigens in the diagnosis of CMV pneumonia is controversial. CMV pp65 antigen assay is based on staining blood neutrophils for the pp65 antigen. The test requires an adequate number of neutrophils (>1,000 cells mm3), so it is not useful in the presence of neutropenia [209]. Another way to quantitatively measure CMV viral load is by detecting the viral DNA by PCR, which could be done on whole blood, plasma, leukocytes, BAL, urine and CSF. Detection of CMV viral DNA in the BAL fluid is suggestive of CMV pneumonia; however, false-positive results are frequent [210]. Detecting blood CMV antigens–by either method– correlates well with CMV pneumonia [211, 212]. However, it is possible for CMV pneumonia to develop without antigenemia [213]. CMV antigens in blood samples may precede clinical features of CMV pneumonia by up to 3  weeks [214]. These tests are also useful in monitoring the response to antiviral therapy. Persistence of CMV antigenemia after 2  weeks of therapy should raise suspicion of antiviral resistance. Gancyclovir as a single agent or in combination with CMV immunoglobulins has been shown to be effective in uncontrolled trials in the treatment of CMV pneumonia and is currently the standard of care in the management of this condition [194, 197]. This is reported in the reviews from Dr. Vigil and from Dr. Sandherr. With this approach, mortality has decreased to 0–47% provided treatment is started prior to the onset of acute respiratory failure. Survival of patients with respiratory failure at the time of initiation of therapy remains infrequent. Prevention of CMV

3  Respiratory Infections in Patients with Hematological Malignancies

infection is the best approach to avoid disease. Use of CMV negative stem cells for HSCT and seronegative or leukocyte-filtered blood products for CMV seronegative recipients decreases the risk of infection to 2–4% [215–217]. Antiviral prophylaxis and viral monitoring with pre-emptive therapy are at present the two main antiviral strategies used in the prevention of CMV infection and disease. Gancyclovir prophylaxis administered in seropositive patients or in seronegative subjects receiving graft from a seropositive donor from 5 days before engraftment to 100 days after HSCT reduces the risk of CMV infection and invasive disease, as well as mortality [218]. However, this approach did not change the overall survival owing to increased sepsis associated with gancyclovir-induced neutropenia and shift in the onset of the CMV disease later in the course following HSCT when the prophylactic treatment is discontinued [219]. Valgancyclovir showed promise as an alternative antiviral agent for preemptive treatment of CMV reactivation following allogeneic HSCT [220]. The use of a cutoff of the number of CMV DNA copies in whole blood samples (10,000 DNA copies/ml) may be useful in avoiding unnecessary antiviral treatment [221]. Other interventions that are under evaluation include infusion of donor-derived CMV-specific cytotoxic T lymphocyte infusion and CMV vaccine [222].

3.6 Community Respiratory Viruses There are four community respiratory viral agents that commonly lead to serious infection in patients with hematological malignancies. These are respiratory syncytial virus (RSV), parainfluenza, influenza and adenovirus. In this book, Schnell and coworkers provide a comprehensive overview on pneumonia related to common viruses in hematological patients. The data on the significance of community respiratory viral infections in this patient population are limited for several reasons, including reports based on small case series, the seasonal nature of the infection that may change the frequency of these infections depending on the time and location of the study, and the fact that many of the patients with community respiratory viral infections are asymptomatic. Nevertheless, there have been recent large studies that improved our understanding of the role of community respiratory viral infections in

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patients with hematological malignancies, especially those who underwent HSCT. Overall, it appears that the incidence of these viral infections in patients with hematological malignancies ranges between 11 and 65% [223–226]. In one study of community respiratory viral infections following HSCT, the main viruses were RSV (35%), parainfluenza (30%), rhinovirus (25%) and influenza virus (11%). Of these, pneumonia occurred in 49% of patients with RSV infection, 22% of those with parainfluenza virus and 3% of rhinovirus infection [227]. In another recent review of 343 cases of community respiratory viral infections in 306 adult patients with hematological malignancies, parainfluenza (mainly type 3) accounted for 27% of infections, influenza (mainly type A) in 33% of infections and RSV in 31% of infections. Community respiratory viral infections progressed to pneumonia in 35% of patients with equal frequency among the three viruses. The patients at high risk for community respiratory viral infections included allogeneic HSCT, leukemia, age older than 65 years, and presence of severe neutropenia or lymphopenia. The overall mortality for community respiratory viral pneumonia was 15%. The only independent predictor of fatal outcome was absolute lymphopenia in patients with influenza pneumonia [226]. The diagnosis of lower respiratory tract community respiratory viral infection is usually suspected in patients with preceding upper respiratory tract infection. The high-resolution CT scan of the chest usually shows patchy or extensive ground-glass opacities, or a mixture of patterns including ground-glass attenuation, thickening of the bronchial walls, and multiple small nodules that may have centrilobular or random distribution. Consolidation and pleural effusions are less common [228]. The diagnosis is usually made using the combination of direct fluorescent antibody (DFA) and indirect fluorescent antibody (IFA) testing, and viral cultures of clinical specimens. The results of the former tests are usually available within 24 h, whereas cultures usually take 7–14 days. The clinical specimens are best obtained by nasopharyngeal wash or swabs. The sensitivity of direct DFA and IFA in detecting infection in patients with hematological malignancies ranges between 20% and 52% [229–231]. BAL fluid may also be helpful when lower respiratory tract infection is suspected with a sensitivity of around 70% [225]. It is important to note in this context that community respiratory viruses are often co-pathogens with other organisms, including bacteria, fungi (such as

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Aspergillus and P. jiroveci) or other viruses (such as CMV) [232]. In one study of community respiratory viral pneumonia, 119 patients had BAL specimens, and 14% had other pathogens cultured [226]. This may create a challenge to clinicians, and every effort should be made to exclude such infections in which community respiratory viruses are isolated. Community respiratory viruses associated with upper respiratory tract infections in patients with hematological malignancies are usually self-limiting and are not associated with increased mortality. However, not uncommonly these patients develop lower respiratory tract infection that is associated with higher mortality [226]. Another potential risk associated with community respiratory viral infections is the development of bronchiolitis obliterans following allogeneic HSCT. In a large series of new-onset airflow obstruction following allogeneic HSCT, one of the main risk factors was respiratory viral infections within the first 100  days following transplantation [233]. Lower respiratory tract parainfluenza [OR 17.9 (95% CI, 2.0–160) and RSV (OR 3.6, 95% CI, 1.0–13)] infections were independent risk factors for development of airflow decline 1 year after allogeneic HSCT [234]. Given the high mortality associated with community respiratory viral lower respiratory tract infections in hematological malignancies, preventive measures play an important role in avoiding infection in these patients. Simple measures such as hand washing are very effective against infection (except for influenza, which is transmitted by aerosolized droplets). In addition, isolating patients suspected to have community respiratory viral infection, even before the infection is confirmed, has been shown to be effective [19]. Symptomatic health-care providers should be restricted from contact with patients with hematological malignancies who are severely immunocompromised [235]. It is also advisable to limit visitors to these patients during the winter months [19].

3.6.1 Respiratory Syncytial Virus (RSV) RSV is one of the most common community respiratory virus infection in patients with hematological malignancies [236–238]. The reported incidence of RSV infection in HSCT recipients ranges between 3.5% and 6.3% and 0.4–1.5% following allogeneic

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and autologous transplantation, respectively [239, 240]. RSV infection usually starts with upper respiratory tract symptoms including cough, rhinorrhea and sinus congestion. Wheezing may develop in 30%; however, fever may not be present even with lower respiratory tract infection [241]. The most serious complication of RSV infection in this patient population is the development of lower respiratory tract infection that happens in up to one third of patients and is associated with high mortality (19%) [226, 242]. Lack of RSV-directed antiviral therapy and older age are associated with increased risk of progression to pneumonia [226]. Other risk factors for RSV pneumonia include male gender, high APACHE II score, protracted lymphopenia and recent corticosteroid therapy [243]. Lower respiratory tract infection is characterized by progressive dyspnea and hypoxemia. The radiological findings of RSV pneumonia include multiple small nodules, bud on tree pattern, diffuse groundglass infiltrates and bronchial thickening [244]. The diagnosis of RSV lower respiratory tract infection could be made by DFA, IFA or PCR of nasopharyngeal or BAL specimens [245]. The role of pharmacological therapy in RSV infection in patients with hematological malignancies remains controversial. Several studies have suggested benefit from ribavirin (intravenously, orally or aerosolized) with or without RSV-specific intravenous immunoglobulins [246, 247]. The efficacy of this treatment once the patient develops acute respiratory failure requiring mechanical ventilation is significantly lower [246]. Delivery of aerosolized ribavirin requires a special machine that is not widely available. Care should be taken during aerosolization of this medication since those who are exposed to it may develop headaches, skin rash and conjunctivitis. Furthermore, ribavirin has teratogenic effects, and pregnant women should not enter the patient’s room during treatment [247]. Other therapeutic modalities, such as high titer monoclonal antibody against RSV, are under investigation [239, 248]. In a recent trial on HSCT, recipients with upper respiratory tract RSV infection were randomized to preemptive aerosolized ribavirin or supportive therapy to prevent progression to lower respiratory tract infection. The intervention was safe and associated with reduced viral load; however, the study could not prove the efficacy of aerosolized ribavirin in preventing progression to lower respiratory tract RSV infection [249].

3  Respiratory Infections in Patients with Hematological Malignancies

3.6.2 Parainfluenza Virus Parainfluenza is another important cause of community respiratory viral infections in patients with hematological malignancies [227, 250, 251]. Parainfluenza has four serotypes, and serotypes 1 and 3 are reportedly the most common causes of infection in these patients. Parainfluenza infection is variable throughout the year, with outbreaks reported in winter, and sometimes in spring and summer. Parainfluenza infection usually presents with cough; however, rhinorrhea and fever are uncommon. Lower respiratory tract infection is the most serious complication of parainfluenza infection and is reported in 18–100% (mean 33%) of patients, with mortality ranging between 15% and 73% (mean 50%) [242]. It is estimated that up to 50% of patients with parainfluenza lower respiratory tract infection have co-infection with bacteria or fungi [251]. The diagnosis of parainfluenza infection is usually made by IFA or DFA and culture of respiratory samples. Real-time PCR is under development and is not available for clinical practice. Treatment of parainfluenza infection is supportive. Ribavirin has activity against parainfluenza and has been shown to be helpful in small studies; [247, 252] however, large studies failed to demonstrate benefit from this therapy [251]. It is recommended to consider aerosolized ribavirin in the treatment of parainfluenza lower respiratory tract infection, although experience to date provides little evidence of efficacy [247].

3.6.3 Influenza Influenza infection has been described in patients with hematological malignancies as a community or nosocomial infection. It develops in the winter months, and the clinical picture is similar to normal hosts with fever, rhinorrhea, coryza, mayalgia and headache. Following HSCT, the frequency of influenza infection is similar with autologous and allogeneic transplantation. In one study of children with cancer, 40% of patients were on chemotherapy, and 63% were lymphopenic. Only one third of the patients were neutropenic [253]. Prognosis is worse in patients with lymphopenia and in those who develop infection early post HSCT [226, 254].

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The treatment of influenza infection is supportive. Antiviral agents, such as amantadine, rimantadine, oseltamivir and zanamivir, may be considered in patients with severe infection [255]. In one report, early treatment with oseltamivir was associated with a trend to less progression to lower respiratory tract infection and decreased viral shedding [254]. Vaccination against influenza is effective; however, live attenuated preparations should be avoided in these patients, and that HSCT recipients may respond poorly to vaccination in the first 2 years following transplantation must be taken into consideration [247]. The pandemic of novel H1N1 influenza is another risk to patients with hematological malignancies. Patients with suspected or confirmed infection should be treated with either oseltamivir or zanamivir. Patients with immunocompromising conditions are advised to receive the inactivated novel H1N1 influenza vaccine [256].

3.6.4 Adenovirus Adenovirus infection accounts for 0–21% of community respiratory viral infections in patients with hematological malignancies and is more common in children [242, 257]. Patients with allogeneic HSCT may have delayed adenovirus-specific T-cell immune recovery, which correlates with increased risk of adenovirus associated morbidity and mortality [258]. App­ roximately 20% of patients with adenovirus infection develop pneumonia [259]. Histologically, the diagnosis is suggested by the presence of the characteristic smudge cells [259]. There are limited antiviral agents with activity against adenovirus. Ribavirin and gancyclovir have no significant activity against this virus [260, 261].

3.6.5 Other Viruses As reported in the paper from Shah and Chemaly, Herpes simplex virus-1 reactivates in the majority of these patients and occasionally may be associated with pneumonia. HHV6 has been suggested to have a role in the pathogenesis of idiopathic pneumonia syndrome following HSCT [262]. It may act as a co-pathogen

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with CMV or as an isolated cause of pneumonia [262]. In a recent report, HHV-6 was isolated from 56.6% of peripheral blood or other specimen tested following HSCT; however, it was associated with interstitial/ alveolar pneumonia in only 2% of patients. HHV-6 reactivation was significantly associated with GVHD, Epstein-Barr viral co-infection, and unrelated donor transplantation [263]. In the chapter from Dr. Schildgen, emerging viral infections are reviewed. Human metapneumovirus is another RNA respiratory virus that has been detected in 3.2% of patients with hematological malignancies. Around half of the patients have pulmonary radiological abnormalities. The prognosis of this infection is good, and the majority of patients do not require antiviral therapy [264].

3.7 Conclusion Patients with hematological malignancies have defects in their immune system that involve one or more of the defense cell lines. These patients are at high risk for a variety of respiratory infectious and noninfectious complications that are related to their underlying malignancies or due to the aggressive therapy of these conditions. There have been significant advances in the diagnosis and management of respiratory infections in patients with hematological malignancies. P. jiroveci and CMV infections are very rare. The treatment of bacterial pneumonias has improved with the availability of broad-spectrum antibiotics. The management of fungal infections, including IPA, is enhanced by the introduction of noninvasive diagnostic methods such as galactomannan assay and better tolerated antifungal agents. Future directions in the management of respiratory infections in patients with hematological malignancies need to focus on more robust and validated noninvasive diagnostic assays that allow for earlier detection and preemptive therapy of fungal and viral infections. Also more emphasis is needed on prevention of respiratory infections. More effective and safer antiviral agents should be another area of research and development as well as the role of combination antimicrobial agents in the management of severe viral and fungal infections. Respiratory infections in patients with hematological malignancies can also be minimized by

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improved treatment regimens including enhanced HSCT techniques that lead to better engraftment and less GVHD. More targeted chemotherapeutic regimens may also decrease the risk of opportunistic infections.

References 1. www.cancer.gov. In: wwwcancergov. Accessed Oct 2009 2. www.ibmtr.org. Accessed Oct 2009 3. Maschmeyer G, Link H, Hiddemann W et  al (1994) Pulmonary infiltrations in febrile patients with neutropenia. Risk factors and outcome under empirical antimicrobial therapy in a randomized multicenter study. Cancer 73(9):2296–2304 4. Soubani AO, Miller KB, Hassoun PM (1996) Pulmonary complications of bone marrow transplantation. Chest 109(4):1066–1077 5. Ewig S, Torres A, Riquelme R et  al (1998) Pulmonary complications in patients with haematological malign­ ancies treated at a respiratory ICU. Eur Respir J 12(1): 116–122 6. Lazarus HM, Vogelsang GB, Rowe JM (1997) Prevention and treatment of acute graft-versus-host disease: the old and the new. A report from the Eastern Cooperative ­Onco­logy Group (ECOG). Bone Marrow Transplant 19(6): 577–600 7. Gerson SL, Talbot GH, Hurwitz S, Strom BL, Lusk EJ, Cassileth PA (1984) Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann Intern Med 100(3):345–351 8. Hofmeister CC, Czerlanis C, Forsythe S, Stiff PJ (2006) Retrospective utility of bronchoscopy after hematopoietic stem cell transplant. Bone Marrow Transplant 38(10): 693–698 9. Paulin T, Ringden O, Lonnqvist B (1985) Faster immunological recovery after bone marrow transplantation in patients without cytomegalovirus infection. Transplantation 39(4):377–384 10. Witherspoon RP, Storb R, Ochs HD et al (1981) Recovery of antibody production in human allogeneic marrow graft recipients: influence of time posttransplantation, the presence or absence of chronic graft-versus-host disease, and antithymocyte globulin treatment. Blood 58(2):360–368 11. Aucouturier P, Barra A, Intrator L et al (1987) Long lasting IgG subclass and antibacterial polysaccharide antibody deficiency after allogeneic bone marrow transplantation. Blood 70(3):779–785 12. Kotloff RM, Ahya VN, Crawford SW (2004) Pulmonary complications of solid organ and hematopoietic stem cell transplantation. Am J Respir Crit Care Med 170(1): 22–48 13. Sloane JP, Depledge MH, Powles RL, Morgenstern GR, Trickey BS, Dady PJ (1983) Histopathology of the lung after bone marrow transplantation. J Clin Pathol 36(5):546–554

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217. Nichols WG, Price TH, Gooley T, Corey L, Boeckh M (2003) Transfusion-transmitted cytomegalovirus infection after receipt of leukoreduced blood products. Blood 101(10):4195–4200 218. Zaia JA (1993) Prevention and treatment of cytomegalovirus pneumonia in transplant recipients. Clin Infect Dis 17(Suppl 2):S392–S399 219. Goodrich JM, Bowden RA, Fisher L, Keller C, Schoch G, Meyers JD (1993) Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant. Ann Intern Med 118(3):173–178 220. Busca A, de Fabritiis P, Ghisetti V et al (2007) Oral valganciclovir as preemptive therapy for cytomegalovirus infection post allogeneic stem cell transplantation. Transpl Infect Dis 9(2):102–107 221. Lilleri D, Gerna G, Furione M, et  al (2007) Use of a DNAemia cut-off for monitoring human cytomegalovirus infection reduces the number of pre-emptively treated children and young adults receiving haematopoietic stem cell transplantation as compared to qualitative pp65-antigenemia. Blood 222. Walter EA, Greenberg PD, Gilbert MJ et  al (1995) Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 333(16): 1038–1044 223. Lujan-Zilbermann J, Benaim E, Tong X, Srivastava DK, Patrick CC, DeVincenzo JP (2001) Respiratory virus infections in pediatric hematopoietic stem cell transplantation. Clin Infect Dis 33(7):962–968 224. Roghmann M, Ball K, Erdman D, Lovchik J, Anderson LJ, Edelman R (2003) Active surveillance for respiratory virus infections in adults who have undergone bone marrow and peripheral blood stem cell transplantation. Bone Marrow Transplant 32(11):1085–1088 225. van Kraaij MG, van Elden LJ, van Loon AM et al (2005) Frequent detection of respiratory viruses in adult recipients of stem cell transplants with the use of real-time polymerase chain reaction, compared with viral culture. Clin Infect Dis 40(5):662–669 226. Chemaly RF, Ghosh S, Bodey GP et al (2006) Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center. Medicine (Baltimore) 85(5):278–287 227. Bowden RA (1997) Respiratory virus infections after marrow transplant: the Fred Hutchinson Cancer Research Center experience. Am J Med 102(3A):27–30, discussion 42-3 228. Franquet T, Rodriguez S, Martino R, Gimenez A, Salinas T, Hidalgo A (2006) Thin-section CT findings in hematopoietic stem cell transplantation recipients with respiratory virus pneumonia. AJR Am J Roentgenol 187(4): 1085–1090 229. Whimbey E, Englund JA, Couch RB (1997) Community respiratory virus infections in immunocompromised patients with cancer. Am J Med 102(3A):10–18, discus­sion 25-6 230. Raboni SM, Nogueira MB, Tsuchiya LR et  al (2003) Respiratory tract viral infections in bone marrow transplant patients. Transplantation 76(1):142–146 231. Bredius RG, Templeton KE, Scheltinga SA, Claas EC, Kroes AC, Vossen JM (2004) Prospective study of respira-

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Part Epidemiology

II

 

4

Epidemiology of Respiratory Events in Patients with HM (Not Including ICU) Georg Maschmeyer

Contents 4.1

Respiratory Events in Patients with Hematological Malignancies.................................. 41

4.2

Lung Infiltrates in Patients with HM.................... 42

4.3

Acute Respiratory Failure in Cancer Patients................................................... 43

References............................................................................ 44

G. Maschmeyer  Department of Hematology, Oncology and Palliative Care, Center for Hematology, Oncology and Radiotherapy, Klinikum Ernst von Bergmann, Charlottenstr. 72, D-14467 Potsdam, Germany e-mail: [email protected]

4.1 Respiratory Events in Patients with Hematological Malignancies Respiratory events, defined as episodes of respiratory symptoms or signs, such as dyspnea, cough, sputum, chest pain, rales, hemoptysis, oxygenation impairment or pulmonary infiltrates on chest radiograph or computed tomography scan, are frequent among patients with hematological malignancies (HM). Almost 50% of patients with acute leukemia undergoing chemotherapy may be affected [10], preferably those with preexisting pulmonary disease and smokers. Also among patients with chronic lymphocytic leukemia, respiratory events are frequent and are likely to take a complicated course caused by the complex immunodeficiency in these patients. Pulmonary events have been reported for up to 58% of patients with malignant lymphoma undergoing high-dose chemotherapy and autologous hematopoietic stem cell transplantation [18], but in general, less than 10% of all autologous stem cell transplant patients will develop pneumonia [27, 30]. The epidemiology of respiratory events has only rarely been investigated using invasive procedures, so that reliable data on specific causes in different subgroups of patients with HM are sparse. Chaoui et al. investigated consecutive patients with newly diagnosed acute leukemia over 1 year to evaluate the incidence and prognostic value of these events and found that the cause of respiratory events was infectious in 34% of cases, an established cause other than infection in 42% and an undetermined cause in 24%. Among patients with undetermined etiology, around 20% were cured by antibiotics and could be considered as probable bacterial pneumonia, increasing the proportion of infectious causes to 55%. Aspergillosis was proven in approximately 10% of cases. The majority of

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_4, © Springer-Verlag Berlin Heidelberg 2011

41

42

respiratory events occurred after starting induction chemotherapy; however, almost all respiratory events of undetermined etiology were present at diagnosis of HM already, and respiratory events of non-infectious origin typically occurred within 10 days of leukemia diagnosis. Among patients with chronic lymphocytic leukemia, pulmonary complications analyzed over a 9-year period were associated with a poor prognosis and a fatality rate of 40% [1]. Notably, 25% of these complications were not caused by pneumonia, but by pleural effusion or lung infiltration by the underlying malignancy (9%), pulmonary leukostasis (4%), secondary malignancies or Richter’s syndrome (3%), or bronchial obstruction (2%). With respect to prognosis, granulocytopenia and renal failure had an unfavorable impact on clinical outcome.

G. Maschmeyer Table 4.1  Drugs potentially associated with pulmonary toxicity in patients with hematological malignancies Alkylating agents   Busulfan   Chlorambucil   Cyclophosphamide Antimetabolites   Azathioprine   Cytosine arabinoside   Fludarabine   Gemcitabine   Methotrexate Cytotoxic antibiotics   Bleomycin   Dactinomycin   Doxorubicin

4.2 Lung Infiltrates in Patients with HM

  Mitomycin Nitrosoureas

In febrile neutropenic patients, lung infiltrates emerge in up to 30% [31]. Clinical outcome deteriorates with increasing patient age, and is particularly dismal in patients with bacteremia and shock as well as in case of delayed appropriate antimicrobial treatment [7, 21]. Infiltrates become apparent in approximately two thirds of cases within 5 days after the onset of fever. As compared with other types of infections, lung infiltrates in neutropenic patients are associated with a higher risk of mortality [3, 15, 26], and their treatment is more difficult and costly [19]. Histopathological findings show that these infiltrates may have numerous different causes, including multi-resistant bacteria [32] and pathogens not susceptible to beta-lactam antibiotics [20], alveolar bleeding, infiltration by the underlying malignancy, cryptogenic organizing pneumonia, immune reconstitution syndrome, and lesions caused by chemotherapy or radiation [2, 4, 8, 13, 14, 35, 36], In particular, the differential diagnosis of drug-induced lung infiltrates should be kept in mind (Table 4.1). Successful clinical response to broad-spectrum antibacterial treatment is observed in less than 30% of patients with pulmonary infiltrates in the course of febrile neutropenia [26, 29], whereas prompt addition of mold-active systemic antifungals increases the response rate to up to 78% [34]. The dramatic

  BCNU (carmustine)   CCNU (lomustine) Assorted agents   Procarbazine   Sirolimus   Taxanes   Vinca alkaloids Modified after Shorr et al. [36]

reduction of lung infiltrates in acute leukemia patients under voriconazole prophylaxis [38], along with histopathological and molecular [20] as well as autopsy studies [4, 9, 17], indicate that the majority of those infiltrates are caused by filamentous fungi, particularly by Aspergillus spp. Clinical outcome of microbiologically or histologically documented invasive aspergillosis in neutropenic patients is poor [12, 22, 28], so that early pre-emptive antifungal treatment is recommended in febrile patients with severe neutropenia and pulmonary infiltrates whose radiological morphology is not typical for non-fungal origin [24, 39]. This recommendation also takes into account that Aspergillus pneumonia will have an unfavorable impact on longterm prognosis and that early institution of systemic

4  Epidemiology of Respiratory Events in Patients with HM (Not Including ICU)

antifungal treatment against Aspergillus spp. improves survival [5, 34]. In patients treated with nucleoside analog, microorganisms typically observed under prolonged cellular immunosuppression, such as cytomegalovirus, mycobacteria or yeasts, must be considered [33], as well as Staphylococcus aureus, Pseudomonas aeruginosa, Aspergillus spp. and pneumococci [1]. Respiratory viruses such as Influenza A or Respiratory Syncytial Virus have occasionally been identified as causes of pulmonary infiltrates in hospitalized, febrile neutropenic patients [23, 37], predominantly during wintertime, but they do not occur more frequently in immunocompromised than in non-immunocompromised patients [16]. Among patients affected, those who are older than 65 years of age or have severe lymphocytopenia may show a mortality rate of 5–15% [11].

43

4.3 Acute Respiratory Failure in Cancer Patients [3] performed a prospective 5-year observational study in a medical intensive care unit treating 203 cancer patients with acute respiratory failure and reported that repiratory failure was mainly due to infectious pneumonia (58%), but also due to lung inflammation due to non-infectious causes in 9% and to congestive heart failure in 12% of patients, whereas no cause was identifiable in 21%. Mortality of HM patients with respiratory events requiring referral to an intensive care unit is high, though decreases over time [10]. Half the patients do not survive their respiratory events (Fig.  4.1). Multivariate analysis shows the type and state of the underlying malignancy [3], proven pulmonary aspergillosis, the

65 patients

30 RE (46%)

35 no RE

Acute respiratory failure 20/30 patients (66%)

Intensive care 12/20 patients

Remain in hematology 8/20 patients

Return to hematology 5/12 patients

Fig. 4.1  Outcome of acute leukemia patients with respiratory events (RE) (end point: death within 45 days of the start of induction chemotherapy) (From [10])

Death in intensive care 7/12 patients

Death in hematology department 9/13 patients

Death from disease progression in hematology department 2 patients

44

G. Maschmeyer

Table 4.2  Multivariable analysis: independent predictors of hospital death in cancer patients with acute respiratory failurea Odds ratio 95% Confidence p Value interval Cause of ARF Congestive heart failure

0.16

0.03–0.72

0.01

Invasive aspergillosis

3.78

1.05–14.24

0.049

No definite diagnosis

3.85

1.26–11.70

0.01

Need for vasopressors

3.19

1.28–7.95

0.01

NIMV only

1.58

0.37–6.70

0.52

NIMV followed by conventional MV

17.46

5.04–60.52

<0.0001

First-line conventional MV

8.75

2.35–32.54

0.001

Late NIMV failureb

10.64

1.05–107.83

0.04

Need for respiratory support

Hosmer–Lemeshow chi-square p value = 0.78 Late NIMV failure: need for conventional MV after 2 full days of NIMV From Azoulay et al. [3] a

b

lack of a definite diagnosis, the need for pressor support and the requirement of invasive mechanical ventilation after failure of non-invasive ventilation as independent poor-risk factors (Table 4.2); however, the prognosis is not unequivocally dismal. In a long-term analysis, it has been demonstrated that at least three unfavorable factors had to be present to clearly predict fatal outcome [25], so that intensive care should be offered to all patients who do not have an unequivocally fatal prognosis. In this book, two papers are dedicated to patient outcome. Dr. Groeger and Dr. Azoulay provide an up-to-date literature analysis, as well as an appraisal of determinants of the outcomes in hematological patients requiring ICU management.

References   1. Ahmed S, Siddiqui AK, Rossoff L, Sison CP, Rai KR (2003) Pulmonary complications in chronic lymphocytic leukemia. Cancer 98:1912–1917   2. Azoulay E, Darmon M, Delclaux C et al (2002) Deterioration of previous acute lung injury during neutropenia recovery. Crit Care Med 30:781–786   3. Azoulay E, Thiery G, Chevret S et al (2004) The prognosis of acute respiratory failure in critically ill cancer patients. Medicine (Baltimore) 83:360–370   4. Bodey G, Bueltmann B, Duguid W et  al (1992) Fungal infections in cancer patients: an international autopsy survey. Eur J Clin Microbiol Infect Dis 11:99–109

  5. Caillot D, Casasnovas O, Bernard A et al (1997) Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin Oncol 15:139–147   6. Camus P, Costabel U (2005) Drug-induced respiratory disease in patients with hematological diseases. Semin Respir Crit Care Med 26:458–81   7. Carratalà J, Rosón B, Fernández-Sevilla A, Alcaide F, Gudiol F (1998) Bacteremic pneumonia in neutropenic patients with cancer: causes, empirical antibiotic therapy, and outcome. Arch Intern Med 158:868–872   8. Cazzadori A, di Perri G, Todeschini G et  al (1995) Transbronchial biopsy in the diagnosis of pulmonary infiltrates in immunocompromised patients. Chest 107:101–106   9. Chamilos G, Luna M, Lewis RE et al (2006) Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period (1989-2003). Haematologica 91:986–989 10. Chaoui D, Legrand O, Roche N et al (2004) Incidence and prognostic value of respiratory events in acute leukemia. Leukemia 18:670–675 11. Chemaly RF, Torres HA, Aguilera EA et  al (2007) Neuraminidase inhibitors improve outcome of patients with leukemia and influenza: an observational study. Clin Infect Dis 44:964–967 12. Cornillet A, Camus C, Nimubona S et al (2006) Comparison of epidemiological, clinical, and biological features of invasive aspergillosis in neutropenic and nonneutropenic patients: a 6-year survey. Clin Infect Dis 43:577–584 13. Danés C, Gonzalez-Martin J, Pumarola T et  al (2002) Pulmonary infiltrates in immunosuppressed patients: analysis of a diagnostic protocol. J Clin Microbiol 40: 2134–2140 14. Daniels CE, Myers JL, Utz JP, Markovic SN, Ryu JH (2007) Organizing pneumonia in patients with hematologic

4  Epidemiology of Respiratory Events in Patients with HM (Not Including ICU) malignancies: a steroid-responsive lesion. Respir Med 101: 162–168 15. Ewig S, Glasmacher A, Ulrich B et  al (1998) Pulmonary infiltrates in neutropenic patients with acute leukemia during chemotherapy. Chest 114:444–451 16. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE (2005) Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 352:1749–1759 17. Groll AH, Shah PM, Mentzel C, Schneider M, Just-Nuebling G, Huebner K (1996) Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J Infect 33:23–32 18. Jules-Elysee K, Stover DE, Yahalom J, White DA, Gulati SC (1992) Pulmonary complications in lymphoma patients treated with high-dose therapy autologous bone marrow transplantation. Am Rev Respir Dis 146:485–491 19. Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH (2006) Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer 106: 2258–2266 20. Lass-Flörl C, Resch G, Nachbaur D (2007) The value of computed tomography-guided percutaneous lung biopsy for diagnosis of invasive fungal infection in immunocompromised patients. Clin Infect Dis 45:e101–e104 21. Lin MY, Weinstein RA, Hota B (2008) Delay of active antimicrobial therapy and mortality among patients with bacteremia: impact of severe neutropenia. Antimicrob Agents Chemother 52:3188–3194 22. Lin SJ, Schranz J, Teutsch SM (2001) Aspergillosis casefatality rate: systematic review of the literature. Clin Infect Dis 32:358–366 23. Martino R, Ramila E, Rabella N et  al (2003) Respiratory virus infections in adults with hematologic malignancies: a prospective study. Clin Infect Dis 36:1–8 24. Maschmeyer G, Beinert T, Buchheidt D et  al (2009) Diagnosis and antimicrobial therapy of pulmonary infiltrates in febrile neutropenic patients. 2008 updated guidelines of the Infectious Diseases Working Party of the German Society of Hematology and Oncology. Eur J Cancer 45:2462–2472 25. Maschmeyer G, Bertschat FL, Häusler E et  al (2003) Outcome analysis of 189 consecutive cancer patients referred to the intensive care unit as emergencies during a 2-year period. Eur J Cancer 39:783–792 26. Maschmeyer G, Link H, Hiddemann W et  al (1994) Pulmonary infiltrations in febrile neutropenic patients. Risk factors and outcome under empirical antimicrobial therapy in a randomized multicenter trial. Cancer 73:2296–2304 27. Mossad SB, Longworth DL, Goormastic M, Serkey JM, Keys TF, Bolwell BJ (1996) Early infectious complications

45

in autologous bone marrow transplantation: a review of 219 patients. Bone Marrow Transplant 18:265–271 28. Pagano L, Caira M, Candoni A et al (2006) The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica 91: 1068–1075 29. Raad II, Whimbey EE, Rolston KVI et al (1996) A comparison of aztreonam plus vancomycin and imipenem plus vancomycin as initial therapy for febrile neutropenic cancer patients. Cancer 77:1386–1394 30. Reich G, Mapara MY, Reichardt P, Dörken B, Maschmeyer G (2001) Infectious complications after high-dose chemotherapy and autologous stem cell transplantation: comparison between patients with lymphoma or multiple myeloma and patients with solid tumors. Bone Marrow Transplant 27:525–529 31. Rossini F, Verga M, Pioltelli P et  al (2000) Incidence and outcome of pneumonia in patients with acute leukemia receiving first induction therapy with anthracycline-containing regimens. Haematologica 85:1255–1260 32. Safdar A, Rolston KV (2007) Stenotrophomonas maltophilia: changing spectrum of a serious bacterial pathogen in patients with cancer. Clin Infect Dis 45:1602–1609 33. Samonis G, Kontoyiannis DP (2001) Infectious complications of purine analog therapy. Curr Opin Infect Dis 14: 409–413 34. Schiel X, Link H, Maschmeyer G (2006) A prospective, randomized multicenter trial of the empirical addition of antifungal therapy for febrile neutropenic cancer patients. Infection 34:118–126 35. Shorr AF, Susla GM, O’Grady NP (2004) Pulmonary infiltrates in the non-HIV-infected immunocompromised patient: etiologies, diagnostic strategies, and outcomes. Chest 125:260–271 36. Suzuki HI, Asai T, Tamaki Z, Hangaishi A, Chiba S, Kurokawa M (2008) Drug-induced hypersensitivity syndrome with rapid hematopoietic reconstitution during treatment for acute myeloid leukemia. Haematologica 93: 469–470 37. Torres HA, Aguilera EA, Mattiuzzi GN et  al (2007) Characteristics and outcome of Respiratory Syncytial Virus infection in patients with leukemia. Haematologica 92:1216–1223 38. Vehreschild JJ, Böhme A, Buchheidt D et al (2007) A double-blind trial on prophylactic voriconazole or placebo during induction chemotherapy for acute myelogenous leukaemia. J Infect 55:445–449 39. Walsh TJ, Anaissie EJ, Denning DW et al (2008) Treatment of aspergillosis: clinical practice guidelines of the Infecti­ ous Diseases Society of America. Clin Infect Dis 46: 327–360

 

5

Epidemiology of Acute Respiratory Failure in Patients with HM (ICU Only) Carlos Agustí, Carmen Lucena, and Antoni Torres

Contents

5.1 Introduction

5.1 Introduction............................................................. 47 5.2 Main Indications for ICU Admission.................... 48 5.3 Etiology of Pulmonary Infections.......................... 5.3.1 Bacterial Infections................................................... 5.3.2 Invasive Fungal Infections........................................ 5.3.3 Cytomegalovirus (CMV).......................................... 5.3.4 Respiratory Viruses...................................................

48 48 49 49 49

5.4 Survival in the ICU................................................. 5.4.1 Selection of Patients................................................. 5.4.2 Transplant Specific Factors....................................... 5.4.3 Ventilatory Support................................................... 5.4.4 Importance of Establishing a Specific Diagnosis..... 5.4.5 Other Factors Influencing Survival...........................

50 51 51 51 52 53

5.5 Conclusions.............................................................. 53 References............................................................................ 54

C. Agustí () Pneumology Department, Clinic Institute of Thorax (ICT), Hospital Clinic of Barcelona – Insitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Ciber de Enfermedades Respiratorias, University of Barcelona (UB), Villarroel 170, 08036 Barcelona, Spain e-mail: [email protected] C. Lucena and A. Torres Pneumology Department, Clinic Institute of Thorax (ICT), Hospital Clinic of Barcelona – Insitut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Villarroel 170, 08036 Barcelona, Spain and Beca Josep Font. Hospital Clínic de Barcelona, Barcelona, Spain e-mail: [email protected]

Great progress has been made in stem cell transplantation over the last years. Most of the progress can be ascribed to an understanding of the human leukocyte antigen (HLA) system for donor selection, immunosuppression for prevention and treatment of graftversus host disease (GVHD), and significant advances in infectious disease prevention, therapy and supportive care. As a result of this progress, the number of potential candidates to receive a transplant has greatly increased, and the survival figures have been progressively encouraging. In fact, the term “hematopoietic stem cell transplantation” (HSCT) has supplanted the previously employed term “bone marrow transplantation” to reflect the broader range of donor stem cell sources available: bone marrow, fetal cord blood, and growth factor-stimulated peripheral blood [1]. Unfortunately, the use of aggressive chemotherapeutic regimens frequently results in life-threatening complications, requiring transfer to the intensive care unit (ICU). Pulmonary complications, both infectious and noninfectious, occur in up to 60% of HSCT recipients, and a significant percentage of them will require ICU admission [1–3]. Infectious complications are more common in allograft recipients because of the requirement of immunosuppressive agents to prevent and treat GVHD. In addition, GVHD itself causes an immunodeficient state. In contrast, noninfectious acute lung injury syndromes (e.g., idiopathic pneumonia syndrome, diffuse alveolar hemorrhage) occur after

Supported by: 2009 SGR 911, Ciber de Enfermedades Res­piratorias (Ciberes CB06/06/0028), el Ciberes es una iniciativa del ISCIII.

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_5, © Springer-Verlag Berlin Heidelberg 2011

47

48

both allogeneic and autologous transplantation with similar frequency [1]. The recognition as well as management of pulmonary complications that result from immunosuppression is a challenging task for clinicians. Although the above-described improvements in patient care have improved the overall survival, once a patient with a hematologic malignancy requires advanced intensive care support, the prognosis worsens significantly with high associated mortality rates, particularly in patients with acute respiratory failure (ARF). Although the survival rate of HSCT recipients admitted to the ICU has been steadily improving, it remains under 50%, with a long-term survival rate under 20% [4].

5.2 Main Indications for ICU Admission It is estimated that 15–30% of the HSCT recipients are admitted to the medical ICU for the management of different complications, with 20% of them requiring mechanical ventilation (MV). In our experience from data collected within a 10-year period [5], 89 patients with hematological malignancies with pulmonary complications were admitted to a respiratory ICU. Fifty-two of 89 (58%) of these patients were HSCT recipients. Patients were admitted to the ICU because of ARF in 61 instances (68%; including 23 patients with acute respiratory distress syndrome, ARDS), sepsis syndrome (12%), pulmonary hemorrhage (9%), heart failure (8%), and miscellaneous conditions (2%). The most common cause of ARF was a pulmonary infection, which was diagnosed in 60% of the patients for whom a specific diagnosis was obtained. Other authors have also found that infection is the most frequent cause of admission to the ICU, particularly in those with neutropenia where up to 80% have a clinically documented infection [6–8]. Also, among organ failures at ICU admission, acute respiratory failure and severe sepsis or septic shock are present in up to 80% of critically ill cancer patients [2, 9] (Table 5.1). Clinical management of infections in critically ill immunocompromised patients is complex since virtually any microorganism may be involved at any time in the evolution, mainly depending on the net state of immunosuppression. The high associated mortality requires a rapid and sometimes invasive diagnostic approach to trying to obtain an etiological diagnosis allowing the early introduction of specific treatment.

C. Agustí et al. Table 5.1  Indications by organ system for ICU admission Respiratory

48%

Sepsis

23%

Cardiac

19%

Neurologic

6%

Bleeding

2%

Others

2%

Modified from ref. [10]

5.3 Etiology of Pulmonary Infections 5.3.1 Bacterial Infections Bacteria are the most frequent cause of pulmonary infections in patients with hematological malignances, accounting for 15–20% of all respiratory infections in HSCT recipients [1] with an associated mortality of 22% [10] (Table 5.2). Different series have shown that bacterial pneumonia is also the most common cause of admission to the ICU in HSCT recipients [11]. One of the problems in diagnosing bacterial pneumonia in hematological patients is the inability to identify the organism in the majority of these patients, which may underestimate the incidence of these infections. Factors that generally increase the risk of bacterial pneumonia following HSCT include pre-transplantation immune status, type of conditioning regimen, and degree and duration of neutropenia [12]. In transplant recipients, bacterial infections may occur at any time in the postTable  5.2  Etiologic diagnosis in HSCT recipients and in haematological patients HSCT Hematologic recipients (%) patients (%) Bacterial

11

23

Fungal

13

19

Polymicrobial

20

8

Other infections

2

4

Pulmonary edema

5

4

DAH

8

4

NOC

3

4

Other non-infections etiologies

7

6

Undetermined

23

28

Modified from ref. [7]

5  Epidemiology of Acute Respiratory Failure in Patients with HM (ICU Only)

transplantation period; however, they seem to be more common in the pre-engraftment phase due to the presence of mucositis and neutropenia. Potential pathogens are myriad. Encapsulated organisms, such as Streptococcus pneumoniae and Haemophilus influenzae, are particularly prevalent; however, many other bacteria must also be considered, particularly Staphyloccocus aureus (including methicillin-resistant, MRSA) and multi-resistant gram-negative bacilli, such as P. aeruginosa [13]. Some epidemiological studies have shown that Legionella sp. pneumonia is more prevalent in the immunocompromised host [14]. It is important to consider that 15–30% of cases ­diagnosed as bacterial pneumonia are mixed ­bacterial/opportunistic infections [11–13]. This fact has to be considered, particularly in patients that do not respond to appropriate specific antibiotic treatment.

49

With regard to Candida infections, with the expanded use of the new antifungal therapies, a higher incidence of infections caused by Candida kruseii and Candida glabrata has been reported [17, 18]. Also infections due to fusarium, Penicillium purpurogenum [19], and Scedosporium prolificans [20, 21] are increasingly being reported. In contrast, a marked decrease in the incidence of P. jiroveci pneumonia has been observed over the last years, mainly because of prescription of specific prophylaxis in patients at risk [22]. In a recent report, P. jiroveci infection was documented in 2.5% of patients undergoing allogeneic HSCT (2.5%). The majority of cases occurred late in the course following HSCT (median 14.5 months) [23] and with a CD4+ count less than 200 cells/mm3.

5.3.3 Cytomegalovirus (CMV) 5.3.2 Invasive Fungal Infections Since neutrophils are the key cells in the defense against aspergillus sp. and other molds, the neutropenic patient and particularly HSCT recipients are at highest risk for dissemination. A steady rise in the documented cases of invasive pulmonary aspergillosis (IPA) post-transplantation has been documented. The risk for IPA is much higher following allogeneic HSCT when compared to autologous transplantation (incidence is 2.3–15% and 0.5–4%, respectively) [15]. Mortality rates for HSCT recipients with IPA have historically been as high as 80%; however, during the past 2 decades, the outcome of this infection seems to be changing. Recently, the Prospective Antifungal Therapy Alliance Registry performed a multicenter study to assess the epidemiology and outcomes of invasive fungal infections in HSCT recipients [16]. In this study, a total of 250 proven or probable invasive fungal infections were included. Almost 70% of the patients had received an allogeneic HSCT, and 31% had received an autologous HSCT. In this series, mortality rates of 21% and 35% at 6 and 12 weeks of diagnosing proven or probable IPA were reported, numbers that are consistent with those reported by other authors, confirming the survival gain evidenced after the inclusion of azoles in the therapeutic armamentarium of invasive fungal infections. Interestingly, the absence of MV or/and hemodialysis was significantly associated with improved survival.

Traditionally, CMV pneumonia has affected 20–35% of HSCT recipients [24], being a common cause of ICU admission. However, the application of antiviral prophylaxis and the systematic use of preemptive therapy have changed the epidemiology of CMV pneumonia in HSCT recipients. Currently, in allogeneic HSCT recipients, the incidence of CMV pneumonia is 10–30% [25]. Also mortality is revised downwards between 30% and 50%. In the pre-prophylaxis era, onset of CMV pneumonia almost invariably occurred between engraftment and day 100. The use of prophylaxis has also shifted the onset of CMV pneumonia in allogeneic HSCT to after the first 100 days, especially in patients with non-myeloablative HSCT and during the treatment of chronic GVHD [26]. Despite improvements in specific treatment, survival of patients with established respiratory failure requiring mechanical ventilation is very poor.

5.3.4 Respiratory Viruses Recent developments in molecular-based diagnostic tools have shown that conventional respiratory viruses [influenza, parainfluenza, respiratory syncitial viruses (RSV), adenoviruses, enteroviruses, and rhinoviruses] may commonly cause respiratory illnesses with significant morbidity and mortality among HSCT recipients. The incidence of these

50

viral infections following HSCT ranges between 11–65% [27]. Upper respiratory tract infections in HSCT recipients are usually self-limiting. However, the progression to pneumonia carries a significant associated mortality. In one study of community respiratory viral infections following HSCT, the main viruses were RSV (35%), parainfluenza (30%), rhinovirus (25%), and influenza virus (11%). Of these, pneumonia occurred in 49% of patients with RSV infection, 22% of those with parainfluenza virus, and 3% of rhinovirus infection [28]. In another recent review of 343 cases of community respiratory viral infections in 306 adults with hema­tological malignancies (mostly HSCT recipients), parainfluenza (mainly type 3) accounted for 27% of infections, influenza (mainly type A) for 33% of infections, and RSV for 31% of infections. Community respiratory viral infections progressed to pneumonia in 35% of patients with equal frequency among the three viruses [27]. Interestingly, community respiratory viruses are often co-pathogens with other organisms, including bacteria, fungi (aspergillus), or other viruses (CMV). Herpes simplex virus 1 reactivates in 80% of HSCT recipients and occasionally may be associated with pneumonia. However, universal prophylaxis with acyclovir and gancyclovir has significantly reduced the incidence [27, 29]. Human herpes virus (HHV-6) may act as a co-pathogen with CMV or act as an isolated cause of pneumonia [30].

5.4 Survival in the ICU In this book, Groeger and colleagues report updated data on outcomes in patients with hematological malignancies admitted to the ICU. Suffering from hematologic malignances is one of the most powerful predictors of mortality due to ARF in the ICU, and this is particularly true when patients with HSCT are considered and when MV is required. For many years, survival was considered dismal, with physicians supporting either denial of ICU admission or considering early treatment limitation decisions. Shuster and Marion [31] found a mortality of 80% in 77 patients treated in the ICU. Our study, evaluating prognostic factors of non-HIV-positive immunocompromised patients with pulmonary complications, showed that

C. Agustí et al.

the mortality rate among HSCT recipients was almost twofold higher than that of patients with hematological malignances or of those who had received solid organ transplants. The requirement of mechanical ventilation was a critical predictor of poor outcome with mortality rates approaching 95% [7]. Long-term survival rates after MV are also dismal in recipients of allogeneic HSCT with active GVHD, with approximately 5% of patients surviving 6 months. Consequently, some clinicians have questioned the utilization of mechanical ventilatory support for these patients. Over the last years, the pessimistic vision of the dismal outcome of hematological patients admitted to the ICU seems to be changing. First, the number of hematological patients requiring further ICU admission or MV has been decreasing [9]. Second, recent series support the notion that the prognosis for hematological patients admitted to the ICU has improved compared to that reported in the 1980s and early 1990s [32, 33]. Benoit et al. [32], evaluating a cohort of 124 patients with a hematologic malignancy admitted to the ICU for a life-threatening complication, observed an ICU and in-hospital mortality of 42% and 54%, respectively. Soubani et  al. [2] evaluated 85 patients admitted to the medical ICU, representing 11.4% of patients who had undergone HSCT during the study period. Fifty-two patients (61%) survived their ICU stay, and 35 patients (41%) were discharged alive from the hospital. The long-term survival rate (>6 months) in this cohort was 28%. Moreover, 19 patients receiving MV (37%) survived their ICU stay, and 33 (97%) patients who did not require MV survived. The study showed short-term and long-term survival rates among adult HSCT recipients who had been admitted to the ICU that were higher than those previously reported. Azoulay et al. [34], in a study evaluating a large group of cancer patients with ARF due to a variety of causes, reported a mortality rate of less than 50%, reaffirming the survival gains achieved in critically ill cancer patients in recent years. Although the above-mentioned results are promising, some factors should lead us to temper this optimistic picture. A recent meta-analysis by Van Gestel et al. [35] in a population of children did not show survival improvement over time when the variable MV was considered. When the specific studies included in this meta-analysis were individually evaluated, it was shown that some of them showed improved survival in

5  Epidemiology of Acute Respiratory Failure in Patients with HM (ICU Only)

ventilated, post-HSCT patients, while others did not show such improvement. Even in those studies that reported improved survival, the need for MV was a strong indicator of worse prognosis. These controversial results may be due to many different variables accounting for survival in hematological patients requiring ICU admission. In the following, we report some of the most determining variables that have been related to survival in HSCT recipients.

51

The number of HSCT recipients requiring ICU admission is decreasing [2]. This lower ratio of admissions is unlikely to be due to the underutilization of ICU resources. Rather, it is probably related to a shorter neutropenic phase, better antimicrobial prophylaxis and treatment, and improved experience in the management of these patients before their condition deteriorates. Also, the improved survival may partially be explained by the implantation of restrictive policies for selecting patients to ICU admission. Although the selection of the best candidates for ICU care is difficult and there are no objective data to support the decision [36], it is possible that selection of patients who are most likely to benefit from ICU admission might explain part of the survival gains. Also, it is possible that the decrease in mortality was, in fact, accompanied by a decrease in the number of patients requiring MV, a known risk factor for poor outcome. Reasons for a decrease in the number of HSCT patients who require MV may be related to a decrease in pulmonary complications in these patients or because hematologists and intensivists are better at the early management of pulmonary complications, thereby minimizing the number of patients who ultimately require MV [3, 37].

administration of immunosuppressive agents after transplantation to prevent or treat GVHD. In addition, GVHD itself causes an immunodeficient state by involving mucosal surfaces, the reticuloendothelial system, and bone marrow. Because of all this, the mortality of recipients of allogeneic HSCT, requiring lifesustaining measures, is extremely high [3, 9]. In contrast, autologous HSCT recipients, who receive a less intense conditioning regimen, have a similar prognosis to other critically ill cancer patients in that their short-term risk of death depends only on the number and type of organ dysfunctions. Few studies have emphasized the radically different outcomes between allogeneic and autologous HSCT recipients in the ICU. Shorr et al. [38] collected data focusing only on autologous HSCT, with the aim of determining the frequency of and risk factors for the use of MV in this population. These authors concluded that MV is infrequently needed following autotransplants. Of 159 patients included, only 17 required MV (10.7%), with 3 of them surviving the episode (17.6%). It is possible that the large proportion of autologous transplantation recipients included in the recently published cohorts might be a confounding factor and led to an underestimation of the mortality rate of allogeneic graft recipients. In particular, the recent series by Soubani et al. [2], which showed a significant improvement in survival in HSCT recipients, included a cohort with almost half of the patients (47%) having received an autologous HSC transplant. Finally, other reasons related to the transplantation technique that can indicate an improved survival are the reduced toxicity of conditioning regimens, the use of alternative hematopoietic precursor sources, such as mobilized peripheral blood stem cells, and cytokines, such as hematopoietic cell colony-stimulating factors, which significantly shorten the time to engraftment, thus decreasing the incidence of infectious pulmonary complications.

5.4.2 Transplant Specific Factors

5.4.3 Ventilatory Support

HSCT recipients have “per se” an adverse prognostic factor in many studies. However the prognosis of both autologous and allogeneic HCT seems to be different. In allogeneic HSCT recipients, infectious complications are more common because they require the

The outcome of alo-HSCT recipients requiring MV has not improved for 2 decades, with consistent survival rates of less than 20% [37, 39, 40] Patients requiring MV have a worse prognosis than similar patients matched for general severity-of-illness

5.4.1 Selection of Patients

52

C. Agustí et al.

scoring systems such as APACHE II, because MV may be directly injurious through increasing the risk for nosocomial pneumonia [41, 42]. Moreover, the association of ARF requiring MV with other organ failures has been reported to be almost uniformly fatal (Fig. 5.1). The avoidance of intubation using ventilatory strategies aimed at minimizing further lung injury may change the dismal prognosis associated with MV in HSCT recipients. Different studies have shown that early implementation of noninvasive ventilation (NIV) is indicated in an early stage of hypoxemic ARF in immunocompromised patients, since it decreases both the requirement of intubation and the incidence of nosocomial pneumonia, and consequently this ventilatory support might improve survival [43–45]. However, caution should be used concerning the unselective use of NIV in immunocompromised patients. Azulay et  al. [34] conducted a prospective study to identify factors associated with death in critically ill cancer patients admitted for ARF. These authors observed that mortality in patients treated with NIV who subsequently did not require conventional MV was only 15%, confirming the critical goal that this technique can add to the management of critically ill cancer patients. However, mortality in patients that required conventional MV after 72 h of NIV was very high. The absence of ­benefit from NIV in patients with severe lung involvement is in agreement with previous reports, suggesting that in selected cases NIV might have a deleterious impact by delaying conventional MV in patients who have ARDS and are managed

with ­nonoptimal ­diagnostic and treatment strategies. Depuydt et al. [46], in a retrospective revision of 26 patients with hematologic malignancies treated with NIV for ARF, could not demonstrate a survival benefit for the use of NIV in comparison with control patients receiving MV and matched for SAPS II. In this study, NIV was mainly used for the treatment of patients with acute severe hypoxic failure, and 60% of them required immediate endotracheal intubation as well as vasopressor therapy because of circulatory shock [45]. They hypothesized that the protective effect of NIV might be exerted only if applied immediately in an early, more compensated phase of their critical illness. In summary, based on the extremely poor prognosis of patients requiring MV and the promising results obtained with NIV, it seems logical to recommend the application of this type of ventilatory support to HSCT recipients with pulmonary infiltrates once significant respiratory failure has ensued. Further studies are needed to confirm these results and to determine the optimal duration of NIV in hematological patients.

5.4.4 Importance of Establishing a Specific Diagnosis HSCT recipients with pulmonary infiltrates need to be managed aggressively, and the underlying etiology must be identified as early as possible. The possibility

50

Frequency of organ failure (%)

45

Fig. 5.1  Differences in the incidence of organ failure between survivors (white segments) and nonsurvivors (black segments) (From [10])

40 35 30 25 20 15 10 5 0 Respirarory*

Cardiovascular*

Renal*

Hepatic*

Neurological*

5  Epidemiology of Acute Respiratory Failure in Patients with HM (ICU Only)

of non-infectious complications and the difficulty of making an antibiotic selection in light of growing resistance and the wide spectrum of potential etiologic factors emphasize the importance of designing strategies aimed at obtaining an early diagnosis. This is particularly true if we consider that inadequacy of the empirical treatment in the ICU setting increases the risk of death significantly [47]. In this sense, it has been shown that early diagnosis of both viral and fungal infections decreases mortality [48]. The use of both non-invasive and bronchoscopic techniques may facilitate the diagnosis in the majority of cases [49]. Some authors advocate the use of non-invasive diagnostic techniques as the cornerstone of the diagnostic workup of these patients, leaving bronchoscopic techniques for those selected patients with no evident risk of deterioration [50]. However, various studies in non-hypoxemic patients outside the ICU have shown that fiberoptic bronchoscopy is a low-risk procedure that can be performed in most patients and may add to the prompt identification of the specific etiologic agent, facilitating an etiology-guided treatment and avoiding unnecessary and potentially harmful additional treatment [51]. More controversial is whether or not the achievement of an early and specific diagnosis improves survival in HSCT recipients admitted to the ICU. Some investigators have reported that obtaining a specific diagnosis does not alter mortality in these patients [52–54]. Other researchers have reached different conclusions [51, 52]. The impact of diagnostic delay on mortality is an important emerging general theme in the care of seriously ill patients, particularly as it affects the adequacy of initial therapy [55]. Recommendations should focus on which is the best diagnostic strategy. In this sense, noninvasive techniques are increasingly used with success in these patients [52]. Bronchoscopy has, no doubt, an important role in the diagnosis, but a diligent analysis of its risk must be performed in each particular patient [52].

5.4.5 Other Factors Influencing Survival Interestingly, in patients who are selected for ICU admission, the characteristics of the underlying malignancy are not associated with survival. Thus, the response to chemotherapy, stage of the malignancy,

53

and other characteristics of the cancer have little or no impact on short-term survival [9]. The importance of leucopenia as a risk factor for mortality in critically ill patients with a hematologic malignancy is controversial. Different studies have reported a higher mortality in patients with prolonged neutropenia; however, this has not been confirmed by other authors [33]. The infectious etiology of the pulmonary complication has been classically considered as the most important cause of mortality in patients with a hematologic malignancy admitted to the ICU [7, 56], however, a recent study by Benoit et al. [8] reported a better prognosis in patients with documented bacterial infection than in those with non-bacterial pulmonary infections. Even in the absence of an identifiable bacterial microorganism, severely ill hematological patients admitted to the ICU with a clinical suspicion of bacterial infection had a better prognosis. Other factors that have been considered as early predictors of poor outcome are the use of vasopressors, high urea levels [33], the number and severity of organ failures [9], liver failure, use of glucocorticoids for treating GVHD, and interval time between transplantation and ICU admission. Although various retrospective analyses in immunocompromised patients indicate that higher APACHE II scores predict mortality [7], extrapolating a specific mortality rate to a particular patient is fraught with difficulty [55]. The information provided by general severity scores should only be considered in light of other clinical and more relevant variables. Finally, some specific complications have been identified as predictors of favorable outcome, such as the engraftment syndrome, congestive heart failure, and diffuse pulmonary hemorrhage [57].

5.5 Conclusions Over the last years, important advances in the management of hematological patients requiring ICU admission have taken place. As a result, survival in these patients has improved over the last decade. Thus, the general reluctance to admit patients with a hematologic malignancy to the ICU, even those with severe critical illness, is currently no longer justified. Not all transplanted patients with ARF can be expected to succumb. In the select, low-risk population of patients with autologous SCT with ARF, survival rates fall

54

within a range that we see for many other diseases that are routinely managed in ICU, such as sepsis-related ARDS [42]. In these patients, dedicated and aggressive support in the early phases of respiratory failure to attempt to establish an etiology seems warranted, allowing the early introduction of specific treatment. Early diagnosis is advantageous, and bronchoscopy, when carefully indicated, substantially increases the diagnostic yield, causing changes in the empirical treatment in the majority of patients [7]. The appropriate timing for withholding or withdrawal of support is probably the most contentious issue surrounding the care of these patients [42]. In patients in whom potential benefits of ICU admission are in doubt, a trial of full intensive ICU management should be given for a limited time period, during which daily evaluation of organ dysfunction may provide a more accurate prediction of survival than at admission [9].

References   1. Kotloff RM, Ahya VN, Crawford SW (2004) Pulmonary complications of solid organ and hematopoietic stem cell transplantation. Am J Respir Crit Care Med 170:22–48   2. Soubani AO, Kseibi E, Bander JJ et al (2004) Outcome and prognostic factors of hematopoietic stem cell transplantation recipients admitted to a medical ICU. Chest 126:1604–1611   3. Pène F, Aubron C, Azoulay E et al (2006) Outcome of critically ill allogeneic hematopoietic stem cell transplantation recipients: a reappraisal of indications for organ failure supports. J Clin Oncol 24:643–649   4. Khassawneh BY, White P Jr, Anaissie EJ et  al (2002) Outcome from mechanical ventilation after autologous peripheral blood stem cell transplantation. Chest 121: 185–188   5. Ewig S, Torres A, Riquelme R et al (1998) Pulmonary complications in patients with haematological malignancies treated at a respiratory ICU. Eur Respir J 12:116–122   6. Darmon M, Azoulay E, Alberti C et al (2002) Impact of neutropenia duration on short-term mortality in neutropenic critically ill cancer patients. Intensive Care Med 28: 1775–1780   7. Rañó A, Agustí C, Benito N et al (2002) Prognostic factors of non-HIV immunocompromised patients with pulmonary infiltrates. Chest 122:253–261   8. Benoit DD, Depydt PO, Peleman RA et  al (2005) Documented and clinically suspected bacterial infection precipitating intensive care unit admission in patients with hematological malignancies: impact on outcome. Int Care Med 31:934–942   9. Darmon M, Azoulay E (2009) Critical care management of cancer patients: cause for optimism and need for objectivity. Curr Opin Oncol 21:318–326

C. Agustí et al. 10. Lossos IS, Breuer R, Or R et al (1995) Bacterial pneumonia in recipients of bone marrow transplantation. A five-year prospective study. Transplantation 60(7):672–678 11. Dunagan DP, Am B, Hurd DD, Haponik EF (1997) Bronchoscopic evaluation of pulmonary infiltrates following bone marrow transplantation. Chest 111:135–141 12. Wingard JR (1999) Opportunistic infections after blood and marrow transplantation. Transpl Infect Dis 1(1):3–20 13. BitMansour A, Burns SM, Traver D (2002) Myeloid progenitors protect against invasive aspergillosis and Pseudomonas aeruginosa infection following hematopoietic stem cell transplantation. Blood 100:4660–4667 14. Haley CE, Cohen ML, Halter J et  al (1979) Nosocomial Legionnaire´s disease: a continuing common source epidemic at Wadsworth Medical Center. Ann Intern Med 90: 583–586 15. Marr KA, Carter RA, Boeckh M, Martin P, Corey L (2002) Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 100(13):4358–66 16. Neofytos D, Horn D, Annaisie E et al (2009) Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry. Clin Infect Dis 48:265–273 17. Wingard J, Merz W, Rinaldi M et al (1991) Increase in candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. N Engl J Med 325:1274–1277 18. Horn DL, Neofytos D, Anaissie EJ et al (2009) Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis 48:1695–1703 19. Lyratzopoulos G, Ellis M, Nerringer R et al (2002) Invasive infection due to penicillium species other than P. marneffei. J Infect 45:184–195 20. Marr KA, Carter RA, Crippa F et al (2002) Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 34:909–917 21. De Hoog GS, Marvin-Sikkema FD, Lahpoor GA et al (1994) Ecology and physiology of the emerging opportunistic fungi Pseudallescheria boydii and Scedosporium prolificans. Mycoses 37:71 22. Kovacs JA, Masur H (2009) Evolving health effects of Pneumocystis: one hundred years of progress in diagnosis and treatment. JAMA 301:2578–2585 23. De Castro N, Neuville S, Sarfati C et al (2005) Occurrence of Pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study. Bone Marrow Transplant 36(10):879–883 24. Sullivan KM, Dykewicz CA, Longworth DL et  al (2001) Preventing opportunistic infections after hematopoietic stem cell transplantation: the Centers for Disease Control and Prevention, Infectious Diseases Society of America, and American Society for Blood and Marrow Transplantation Practice Guidelines and beyond. Hematology Am Soc Hematol Educ Program 2001:392–421 25. Taplitz RA, Jordan MC (2002) Pneumonia caused by herpes viruses in recipients of hematopoietic cell transplants. Semin Respir Infect 17:121–129 26. Boeckh M, Leisenring W, Riddell SR et al (2003) Late cytomegalovirus disease and mortality in recipients of allogeneic

5  Epidemiology of Acute Respiratory Failure in Patients with HM (ICU Only) hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Blood 101:407–414 27. Chemaly RF, Ghosh S, Bodey GP et al (2006) Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center. Medicine (Baltimore) 85: 278–287 28. Bowden RA (1997) Respiratory virus infections after marrow transplant: the Fred Hutchinson Cancer Research Center experience. Am J Med 102:27–30, discussion 42-3 29. Fischer SA (2008) Emerging viruses in transplantation: there is more to infection after transplant than CMV and EBV. Transplantation 86:1327–1339 30. Buchbinder S, Elmaagacli AH, Schaefer UW, Roggendorf M (2000) Human herpesvirus 6 is an important pathogen in infectious lung disease after allogeneic bone marrow transplantation. Bone Marrow Transplant 26:639–44 31. Schuster DP, Marion JM (1983) Precedents for meaningful recovery during treatment in a medical intensive care unit. Am J Med 75:402–408 32. Benoit DD, Vandewoude KH, Decruyenaere JM, Hoste EA, Colardyn FA (2003) Outcome and early prognostic indicators in patients with a hematologic malignancy admitted to the intensive care unit for a life-threatening complication. Crit Care Med 31:104–112 33. Dane N, Maziarz RT, Haupt MT (1999) Mechanical ventilation in hematopoietic stem cell transplant patients: is there need for re-evaluation? Chest 116:857–859 34. Azoulay E, Thièry G, Chevret S et al (2004) The prognosis of acute respiratory failure in critically ill cancer patients. Medicine 83:360–370 35. Van Gestel J, Bollen C, Van der Tweel I et al (2008) Intensive care unit mortality trends in children after hematopoietic stem cell transplantation: a meta-regression analysis. Crit Care Med 36:2898–2904 36. Thiery G, Azoulay E, Darmon M et al (2005) Outcome of cancer patients considered for intensive care unit admission: a hospital-wide prospective study. J Clin Oncol 23: 4406–4413 37. Parker RI (2008) Paediatric intensive care unit outcome following paediatric hematopoietic stem cell transplantation: Quo Vadis? Crit Care Med 36:2954–2955 38. Shorr AF, Moores LK, Edenfield WJ et  al (1999) Mechanical ventilation in hematopoietic stem cell transplantation. Can we effectively predict outcomes? Chest 116:1012–1018 39. Bach PB, Schrag D, Nierman DM et al (2001) Identification of poor prognostic features among patients requiring mechanical ventilation after hematopoietic stem cell transplantation. Blood 93:3234–3240 40. Price KJ, Thall PF, Kish SK et al (1998) Prognostic indicators for blood and marrow transplant patients admitted to an intensive care unit. Am J Respir Crit Care Med 158: 876–884 41. Nichols DJ, Maziarz RT, Haupt MT (1999) Mechanical ventilation in hematopoietic stem cell transplant recipients: is there need for reevaluation? Chest 116:857–859

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42. Esteban A, Anzueto A, Frutos F et al (2002) Characteristics and outcomes in adult patients receiving mechanical ventilation. A 28-day international study. JAMA 287:345–355 43. Antonelli M, Conti C, Rocco M et al (1998) A comparison of noninvasive positive-pressure ventilation and conventional mechanical ventilation in patients with acute respiratory failure. N Engl J Med 339:429–435 44. Hilbert G, Gruson D, Vargas F et  al (2001) Noninvasive ­ventilation in immunocompromised patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med 95:358–364 45. Azoulay E, Alberti C, Bornstain C et  al (2001) Improved survival in cancer patients requiring mechanical ventilatory support: impact of noninvasive mechanical ventilatory support. Crit Care Med 29:519–525 46. Depuydt PO, Benoit DD, Vandewoude KH et  al (2004) Outcome in noninvasively and invasively ventilated hematologic patients with acute respiratory failure. Chest 126: 1299–1306 47. Ibrahim EH, Sherman G, Ward S et al (2000) The influence of inadequate antimicrobial treatment of blood stream infections on patient outcomes in the ICU setting. Chest 118: 146–155 48. Elizaga J, Olavarria E, Apperley JF et al (2001) Parainfluenzae virus 3 infection after stem cell transplant: relevance to outcome of rapid diagnosis and ribavirin treatment. Clin Infect Dis 32:413–418 49. Rañó A, Agustí C, Jiménez P et al (2001) Pulmonary infiltrates in non-HIV immunocompromised patients: a diagnostic approach using non-invasive and bronchoscopic procedures. Thorax 56:379–387 50. Azoulay E, Mokart D, Rabbat A et  al (2008) Diagnostic bronchoscopy in hematology and oncology patients with acute respiratory failure: prospective multicenter data. Crit Care Med 36:100–107 51. Shorr AF, Susla GM, O’Grady NP (2004) Pulmonary infiltrates in the non-HIV-infected immunocompromised patient: etiologies, diagnostic strategies and outcomes. Chest 125: 260–271 52. White D, Bonacum JT, Miller CB (1997) Utility of fiberoptic bonchoscopy in bone marrow transplant patients. Bone Marrow Transplant 20:681–687 53. Murray PV, O´Brien ME, Padhani AR et  al (2001) Use of first line bronchoalveolar lavage in the immunosuppressed oncology patient. Bone Marrow Transplant 27:967–71 54. Poe RH, Wahl GW, Qazi R et al (1986) Predictors of mortality in immunocompromised patients with pulmonary infiltrates. Arch Intern Med 146:1304–1308 55. Shorr AF, Kollef MH (2002) The quick and the dead: the importance of rapid evaluation of infiltrates in the immunocompromised patient. Chest 122:9–12 56. Groeger JS, White P, Nierman DM et al (1999) Outcome for cancer patients requiring mechanical ventilation. J Clin Oncol 17:991–997 57. Lee CK, Gingrich RD, Hohl RJ et al (1995) Engraftment syndrome in autologous bone marrow and peripheral stem cell transplantation. Bone Marrow Transplant 16:175–182

 

6

Noninfectious Lung Involvement in Patients with Hematological Malignancies (Excluding BMT) Bernard Maitre

Contents

6.1 Epidemiology

6.1 Epidemiology........................................................... 57 6.2 Venous Thromboembolism in the Hematologic Malignancies..................................... 6.2.1 Lymphoma................................................................ 6.2.2 Acute Leukemia........................................................ 6.2.3 Multiple Myeloma....................................................

57 58 58 58

6.3 Drug-Induced Lung Toxicity................................. 58 6.4 Lung Diseases Induced by Radiation of the Chest.............................................................. 59 6.5 Secondary Lung Cancers....................................... 60 6.5.1 Hodgkin’s Lymphoma.............................................. 60 6.5.2 Second Cancers Following Bone Marrow Transplantation............................................ 60 6.6 Other Lung Diseases............................................... 6.6.1 Pulmonary Extramedullary Hematopoiesis.............. 6.6.2 Pulmonary Hypertension and Myelofibrosis............ 6.6.3 Alveolar Proteinosis..................................................

61 61 61 61

6.7 Summary................................................................. 61 References............................................................................ 62

B. Maitre  Service de Pneumologie, Hôpitaux Henri Mondor et intercommunal, Créteil, Université Paris XII, PRES EST France e-mail: [email protected]

Patients with hematological malignancies frequently experience pulmonary diseases, and these complications represent a difficult challenge for physicians. The aim of this chapter is not to give an exhaustive review of noninfectious causes of lung involvement in these patients, but to highlight the frequency of some of well-known lung diseases. We have made the choice to examine three different aspects of noninfectious lung involvement in hematological patients that are also covered in three different chapters in this book, namely, thromboembolism, secondary cancers and treatmentrelated pulmonary toxicity. Our major goal is to ­illu­strate the wide spectrum of lung diseases in hematological patients.

6.2 Venous Thromboembolism in the Hematologic Malignancies Patients with hematological malignancies are well known to be at high risk of hemorrhagic complications, but are also at high risk of venous thromboembolism (VTE) [11]. Dr. Khorana has contributed a specific chapter on this topic in this book. Compared with the estimated annual incidence of VTE in the general population, the incidence of 0.1–0.5% in the cancer population appears in the ranges of VTE in patients with high-risk solid tumors [18]. Immobility, age, previous thrombotic history, venous stasis and infection are all disease-host risk factors for VTE. Treatment-related risk factors, such as chemotherapy, hormone therapy, erythropoiesis-stimulating factor or central venous devices, can participate to the general risk [15].

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_6, © Springer-Verlag Berlin Heidelberg 2011

57

58

Current published data allow estimation of VTE rates in patients with lymphoma, acute leukemia (AL) and multiple myeloma (MM).

6.2.1 Lymphoma In a large cohort study from Khorana et al., lymphoma was associated with the third risk level of thrombosis after upper gastrointestinal cancers and lung cancers [15]. The retrospective analysis from [24] found a global VTE incidence of 7.7%, with a significantly higher rate in patients with high-grade lymphoma (10.6%). The thrombosis incidence is even higher in CNS lymphoma patients mostly receiving methotrexate (59.5%) [12]. Two studies have prospectively evaluated the incidence of VTE in lymphoma. The VTE rate was estimated between 6.6% and 8.6% depending on the type of lymphoma (Hodgkin’s disease versus non-Hodgkin’s lymphoma) and chemotherapy regimens [15, 26]. A platelet count higher than 350,000 mm3 and vessel compression by the tumor were risk factors for VTE.

6.2.2 Acute Leukemia Thrombotic events have been described to be less ­frequent than hemorrhages in AL patients, particularly in acute promyelocytic leukemia. However, recent studies suggest a significant rate of thrombosis, which can vary from 1.4% to 12% depending on the timing: at diagnosis or during remission induction therapy. A large population-based cohort study of patients with AL, AML or ALL was used to determine the incidence and risk factors associated with development of VTE. The 2-year cumulative incidence of VTE was 5.2% in AML and 4.5% in ALL [17]. In AML patients, female sex, older age, number of chronic comorbidities, and presence of a catheter were significant predictors of development of VTE within 1 year. A diagnosis of VTE was not associated with reduced survival in AML patients. Risk factors for VTE in ALL patients were presence of a central venous catheter, older age and number of chronic comorbidities. In the patients with ALL, development of VTE was associated with a 40% increase in the risk of dying within 1 year. In acute lymphoid leukemia, two meta-analyses found an incidence of 5.2% (children) to 5.9% (adults) of thrombotic events [5, 6].

B. Maitre

6.2.3 Multiple Myeloma Ten percent of patients with MM will develop a VTE. Thalidomide and its derivative increase the response of treatment, but when these drugs are associated with doxorubicin or dexamethasone, the risk of VTE is two or three times more likely [3, 10]. Few data are available for lenalidomide, but it seems associated with an increase of thrombotic events, particularly in combination with dexamethasone (6% vs. 2%) [22]. A recent study combining results and follow-up of two randomized protocols, including 353 patients with MM, showed a thromboembolic event in 17% of patients. However, contrary to patients with solid cancer, it is not associated with shorter survival [32].

6.3 Drug-Induced Lung Toxicity Infiltrative lung diseases related to the use of antineoplastic agents are being increasingly described in patients with hematological malignancies. A chapter from Camus and coworkers covers this topic very well in this book. Although the pulmonary toxicity of old agents is well known, they contribute little to significant pulmonary disease. However, newer drugs or old drugs with new indications (such as thalidomide in MM) increase the incidence of such complications substantially. Regarding epidemiological data, conversely to VTE, no specific diagnostic criteria are set up to report on precise the incidence of drug-induced lung diseases. Drugs can produce all histological patterns of interstitial pneumonia, and there are no specific histological criteria for drug-induced lung disease. The diagnosis rests on a temporal association between exposure and the development of respiratory symptoms. Since patients with hematological malignancies are often being treated at the same time by different antineoplastic drugs or exposed to a wide variety of others medications, with potential lung toxicity, increased difficulties exist when trying to affirm the relation between one drug and lung toxicity. The incidence of drug-induced lung toxicities varies considerably from 0.1% to 15% of patients with hematological malignancies. It has to be noted that concomitant use of steroids does not necessarily prevent the development of lung toxicities (Table 6.1).

6  Noninfectious Lung Involvement in Patients with Hematological Malignancies (Excluding BMT)

59

Table 6.1  Antineoplastic agents associated with lung disease Agent

Class

Incidence

Frequency

Anthracyclines

Cytotoxic antibiotics

<0.1

Azacytidine

Demethylating agent

<5

Bleomycin

Antineoplastic antibiotic

Bortezomib

Proteasome inhibitor

Busulfan

Alkylating agent

c

Carmustine

Nitrosourea

c

Cladribine

Purine analog

Cyclophosphamide

Alkylating agent

c

Cytosine Arabinoside

Antimetabolite analog

b

Dasatinib

Tyrosine kinase inhibitor

Etoposide

Topoisomerase inhibitor

Fludarabine

Purine analog

Gemcitabine

Antimetabolite

b

Hydroxyurea

Antimetabolite

b

Imatinib

Tyrosine kinase inhibitor

<1.3

a

Interferon-alpha

Interferon

1.5

b

Lenalidomine

Thalidomide derivative

6

a

Lomustine

Nitrosourea

b

Melphalan

Alkylating agent

b

Methotrexate

Antimetabolite agent

c

Procarbazine

Alkylating agent

<0.1

b

Rituximab

Monoclonal antibody

<0.1

b

Thalidomide

Thalidomide

<0.1

a

Trofosfamide

Alkykating agent

<0.1

a

Vinblastine

Vinca alkaloid

a c

15

<0.1

<0.1

a

a

b c

<9

b

c

Pneumotox® website [4] a Isolated cases b 10 cases reported c 20–100 cases reported Adapted from http://pneumotox.com

6.4 Lung Diseases Induced by Radiation of the Chest Radiation lung toxicity can develop during or following radiation therapy for Hodgkin’s or non-Hodgkin’s lymphoma, or total body irradiation (TBI). Gallego and Rello have covered this topic very nicely in this book. Variation in study population, treatment regimen

and criteria for radiation pneumonia diagnosis hampers the comparison of patient cohorts across different studies. In contrast to allogeneic BMT studies, the incidence of pneumonitis is low (between 0% and 16%). In a study of 94 patients who underwent BMT using an escalated TBI-containing conditioning regimen, Chen and coworkers looked at pretransplant variables that predict radiation-induced pneumonitis [7]. They failed to find predictable variables other than

60

pretransplant hemoglobin less than 100 g/L. This suggests that TBI itself is the main factor, and this has been confirmed by comparison with others cohorts of patients with lymphoma who have been treated by the same conditioning regimen with or without TBI [7]. This has been confirmed in patients with MM. Unacceptable risk of pulmonary fibrosis has been described in regimens combining radiation and drugs, such as gemcitabin, vinblastin, bleomycin and methotrexate. However, in one study of 60 early stage Hodgkin’s lymphoma (HL) patients receiving an ABVD regimen, adding mediastinal radiotherapy was associated with a significant decrease in FVC and DLCO. This worsening respiratory function was observed in 37% of patients, but with no translation into clinical symptoms [14]. Mediastinal emphysema and pneumothorax have also been described in case series, and a frequency of 2.2% has been proposed for Hodgkin’s patient without previous lung disease and treated by mantle radiation therapy [27, 28]. This suggests a pathophysiologic link between apical fibrosis and onset of pneumothorax. Strikingly, most patients were asymptomatic. Radiation can also cause vasculopathy with intimal damage in both arterioles and veinules. Different case reports have emphasized the risk of veno-occlusive disease of the liver but also the lung following TBI and a conditioned regimen before bone marrow transplantation, but case reports described this complication in patients following radiation in a mantle distribution [16, 19].

6.5 Secondary Lung Cancers Although the possibility of a malignant involvement in different organs is possible and frequent in hematological malignancies, secondary malignancy as a result of long-term complications of treatment is one of the most concerning problems for physicians.

6.5.1 Hodgkin’s Lymphoma Solid tumors account for more than one-half of second malignancies developing after 15 or more years of follow-up in patients treated for HL. Although no

B. Maitre

prospective study has reported the occurrence of a new second cancer, 20 retrospective studies with long-term outcomes have been published [20]. In this study, relative risk and absolute excess risk of second malignant disease in 32,591 patients treated for HL were as ­follows: for all solid tumors, RR 2.0 (1.9–2.4) and absolute excess risks of 33.1; for esophagus, 2.8 (1.8–4.0) and 0.7, for stomach, 1.5 (0.3–3.5) and 0.1; for small intestine 1.9 (1.5–2.4) and 1.5; for colon, 2.9 (2.6–3.2) and 9.7; for the lung 1.6 (1.4–1.9) and 2.0; for female breast, 9.9 (8.7– 11.2) and 8.8 [20]. Lung cancer frequencies varied across studies: 1/3 of solid tumors in the British National Lymphoma Organization and less than 10% in the American study [29, 30]. Risk of lung cancer is significantly increased in patients who have been treated for HL[21, 25]. The median relative risk of a second lung cancer ranges from 2.6 to 7. Several risk factors have been described: (1) age at treatment older than 45 years; (2) time since treatment, but above 20–30 years after treatment the risk falls to that of the untreated population; (3) the treatment modality is an important risk factor: an increased number of cycles >9 or a MOPP regimen; radiotherapy is a more important factor than chemotherapy itself, increasing the radiation dose up to 40 Gy; (4) the smoking habit, smoking at the time of treatment or current smokers can increase the risk for lung cancer [30], but not the amount smoked before diagnosis [31]. There appears to be a more than multiplicative relation between smoking-related and radiationrelated or alkylating agent risk (Table 6.2). Contrarily, gender, splenic involvement or splenectomy and combined modality do not appear to be associated with a high risk.

6.5.2 Second Cancers Following Bone Marrow Transplantation In the largest study conducted to date among 19,229 recipients of allogeneic and syngeneic HCT, the cumulative incidence of second cancers at 5, 10 and 15 years after transplantation was 0.7%, 2.2% and 6.7%, respectively. In the general population, these rates are of 0.3%, 0.6% and 0.8% [23].

6  Noninfectious Lung Involvement in Patients with Hematological Malignancies (Excluding BMT)

61

Table 6.2  Risk of developing lung cancer in Hodgkin’s lymphoma patients depending on treatment regimens and smoking habits Relative risk [95% CI] Radiation > 5 Gy Alkylating agents Smoking habits in the 5 years before diagnosis of lung cancer −

−

–

1.0a

−

+

−

4.3 [2–12]

−

−

+

6.0 [2–20]

+

−

−

7.2 [3–21]

+

+

−

7.2 [3–22]

–

+

+

16.8 [6–53]

+

−

+

20.2 [7–68]

+

+

+

49.1 [15–187]

Data from Travis et al. [30] a The reference group consisted of 21 patients with lung cancer and 98 control patients who received a radiation dose of less than 5 Gy to the specific location in the lung where the cancer was diagnosed

6.6 Other Lung Diseases

6.6.3 Alveolar Proteinosis

6.6.1 Pulmonary Extramedullary Hematopoiesis

In a retrospective study, Fleury Feith and colleagues estimated the incidence of this rare complication at 5.3% among all the hematologic population and 10% in patients with myeloid disorders [8]. The study is based on a BAL retrospective study, but may represent in most cases a more surfactant dysfunction than a lung disease. Alveolar proteinosis is covered by the contribution to this book by Vincent and Tandjaoui.

Acute respiratory failure and pulmonary fibrosis have been described in patients with agnogenic myeloid metaplasia, but parenchymal nodules and pleural effusion have been described as well [1, 2].

6.6.2 Pulmonary Hypertension and Myelofibrosis An association between pulmonary hypertension and myeloproliferative diseases has been suggested in small series [9]. For these reasons, it is difficult to estimate the incidence of this complication, but it is probably a rare disease. It has been suggested that there are two distinct forms of pulmonary hypertension [13]. Chronic thromboembolism disease is a common complication of myeloproliferative disease and can induce pulmonary hypertension. This form of pulmonary hypertension occurred more frequently in the first 2  years. Arterial pulmonary hypertension seems less frequent and occurred in a late course of the disease, suggesting that myeloid infiltration participates in the physiopathology.

6.7 Summary Noninfectious lung involvement in patients with hematological malignancies is a frequent condition. If infectious disease and cardiogenic pulmonary edema are the most frequent complications, VTE and druginduced lung toxicity could potentially be detected early during the hematological disease. Risk of lung cancers is significantly increased in patients with CLL, those treated for lymphoma or those who underwent bone marrow transplantation. This emphasized the need to encourage patients to stop smoking, and a screening program for lung cancer in high-risk patients (age >45 years, chest irradiation and smokers) should be discussed.

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References   1. Asakura S, Colby TV (1994) Agnogenic myeloid metaplasia with extramedullary hematopoiesis and fibrosis in the lung. Report of two cases. Chest 105:1866–1868   2. Bartlett RP, Greipp PR, Tefferi A et al (1995) Extramedullary hematopoiesis manifesting as a symptomatic pleural effusion. Mayo Clin Proc 70:1161–1164   3. Baz R, Li L, Kottke-Marchant K et  al (2005) The role of aspirin in the prevention of thrombotic complications of thalidomide and anthracycline-based chemotherapy for multiple myeloma. Mayo Clin Proc 80:1568–1574   4. Camus P, Foucher P Pneumotox® website (1997) Last update 2009 http//pneumotox.com.   5. Caruso V, Iacoviello L, Di Castelnuovo A et al (2007) Venous thrombotic complications in adults undergoing induction treatment for acute lymphoblastic leukemia: results from a meta-analysis. J Thromb Haemost 5:621–623   6. Caruso V, Iacoviello L, Castelnuovo D et  al (2006) Thrombotic complications in childhood acute lymphob­lastic leukemia: a meta-analysis of 17 prospective studies comprising 1, 752 pediatric patients. Blood 108:2216–2222   7. Chen CI, Abraham R, Tsang et  al (2001) Radiationassociated pneumonitis following autologous stem cell transplantation: predictive factors, disease characteristics and treatment outcomes. Bone Marrow Transplant 27: 177–182   8. Cordonnier C, Fleury-Feith J, Escudier E et  al (1994) Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients. Am J Respir Crit Care Med 149:788–794   9. Dingli D, Utz JP, Krowka MJ et al (2001) Unexplained pulmonary hypertension in chronic myeloproliferative disorders. Chest 120:801–808 10. El Accaoui RN, Shamseddeen WA, Taher AT (2007) Thalidomide and thrombosis. A meta-analysis. Thromb Haemost 97:1031–1036 11. Falanga A, Marchetti M (2009) Venous thromboembolism in the hematologic malignancies. J Clin Oncol 27: 4848–4857 12. Goldschmidt N, Linetsky E, Shalom E, Varon D, Siegal T (2003) High incidence of thromboembolism in patients with central nervous system lymphoma. Cancer 98: 1239–1242 13. Guilpain P, Montani D, Damaj G et  al (2008) Pulmonary hypertension associated with myeloproliferative disorders: a retrospective study of ten cases. Respiration 76:295–302 14. Hirsch A, Vander Els N, Straus DJ et al (1996) Effect of ABVD chemotherapy with and without mantle or mediastinal irradiation on pulmonary function and symptoms in early-stage Hodgkin’s disease. J Clin Oncol 14: 1297–1305 15. Khorana AA, Francis CW, Culakova E et  al (2005) Risk ­factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer 104: 2822–2829

B. Maitre 16. Kramer MR, Estenne M, Berkman N et al (1993) Radiationinduced pulmonary veno-occlusive disease. Chest 104: 1282–1284 17. Ku GH, White RH, Chew HK et al (2009) Venous thromboembolism in patients with acute leukemia: incidence, risk factors, and effect on survival. Blood 113:3911–3917 18. Lee AY, Levine MN (2003) Venous thromboembolism and cancer: risks and outcomes. Circulation 107:I17–21 19. Lombard CM, Churg A, Winokur S (1987) Pulmonary venoocclusive disease following therapy for malignant neoplasms. Chest 92:871–876 20. Lorigan P, Radford J, Howell A et  al (2005) Lung cancer after treatment for Hodgkin’s lymphoma: a systematic review. Lancet Oncol 6:773–779 21. Mauch PM, Kalish LA, Marcus KC et  al (1996) Second malignancies after treatment for laparotomy staged IA-IIIB Hodgkin’s disease: long-term analysis of risk factors and outcome. Blood 87:3625–3632 22. Menon SP, Rajkumar SV, Lacy M et  al (2008) Thromboembolic events with lenalidomide-based therapy for multiple myeloma. Cancer 112:1522–1528 23. Metayer C, Curtis RE, Vose J et al (2003) Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-control study. Blood 101:2015–2023 24. Mohren M, Markmann I, Jentsch-Ullrich et  al (2006) Increased risk of venous thromboembolism in patients with acute leukaemia. Br J Cancer 94:200–202 25. Ng AK, Bernardo P, Weller E et al (2002) Second malignancy after Hodgkin disease treated with radiation therapy with or without chemotherapy: long-term risks and risk factors. Blood 100:1989–1996 26. Ottinger H, Belka C, Kozol et al (1995) Deep venous thrombosis and pulmonary artery embolism in high-grade non Hodgkin’s lymphoma: incidence, causes and prognostic relevance. Eur J Haematol 54:186–194 27. Pezner RD, Horak DA, Sayegh HO et al (1990) Spontaneous pneumothorax in patients irradiated for Hodgkin’s disease and other malignant lymphomas. Int J Radiat Oncol Biol Phys 18:193–198 28. Shapiro SJ, Shapiro SD, Mill WB et al (1990) Prospective study of long-term pulmonary manifestations of mantle irradiation. Int J Radiat Oncol Biol Phys 19:707–714 29. Swerdlow AJ, Douglas AJ, Hudson GV et al (1992) Risk of second primary cancers after Hodgkin’s disease by type of treatment: analysis of 2846 patients in the British National Lymphoma Investigation. BMJ 304:1137–1143 30. Travis LB, Gospodarowicz M, Curtis RE et al (2002) Lung cancer following chemotherapy and radiotherapy for Hodgkin’s disease. J Natl Cancer Inst 94:182–192 31. van Leeuwen FE, Klokman WJ, Stovall M et al (1995) Roles of radiotherapy and smoking in lung cancer following Hodgkin’s disease. J Natl Cancer Inst 87:1530–1537 32. Zangari M, Tricot G, Polavaram L et  al (2010) Survival effect of venous thromboembolism in patients with multiple myeloma treated with lenalidomide and high-dose dexamethasone. J Clin Oncol 28:132–135

7

Noninfectious Pulmonary Involvement in Hematopoietic Stem Cell or Bone Marrow Transplant Recipients Bekele Afessa

Contents 7.1 Introduction............................................................. 63 7.2 Pulmonary Function Abnormalities..................... 64 7.3 Asthma..................................................................... 66 7.4 Acute Pulmonary Edema....................................... 66 7.5 Bronchiolitis Obliterans......................................... 7.5.1 Incidence and Risk Factors....................................... 7.5.2 Pathogenesis............................................................. 7.5.3 Clinical Findings and Diagnostic Evaluation........... 7.5.4 Treatment.................................................................. 7.5.5 Clinical Course......................................................... 7.6 Bronchiolitis Obliterans Organizing Pneumonia (BOOP)................................................ 7.6.1 Incidence and Pathogenesis...................................... 7.6.2 Clinical Presentation and Diagnostic Evaluation................................................................. 7.6.3 Treatment and Prognosis.......................................... 7.7 Idiopathic Pneumonia Syndrome (IPS)................ 7.7.1 Epidemiology............................................................ 7.7.2 Clinical Findings and Diagnostic Evaluation........... 7.7.3 Treatment.................................................................. 7.7.4 Clinical Course and Prognosis..................................

66 66 67 67 68 69

7.12 Pulmonary Veno-Occlusive Disease (PVOD)....... 7.12.1 Pathogenesis............................................................. 7.12.2 Clinical Findings and Diagnostic Evaluation........... 7.12.3 Treatment and Prognosis..........................................

74 74 74 75

7.13 Other Pulmonary Complications.......................... 7.13.1 Pulmonary Arterial Hypertension............................. 7.13.2 Pulmonary Alveolar Proteinosis............................... 7.13.3 Chronic Eosinophilic Pneumonia.............................

75 75 75 76

References............................................................................ 76

70 71

7.1 Introduction

71 71 71 71 72

Worldwide, tens of thousands of patients undergo blood and marrow transplants (BMT) each year, mainly for hematologic disorders [1]. BMT recipients are often treated with a conditioning regimen before the transplant. Conditioning regimens with total body irradiation ³500 cGY, single fractionated dose ³800 cGY, busulfan doses of >9 mg/kg, or malphalan doses of >150 mg/m2 given as single agents or in combination with other agents are considered myeloablative. Conditioning regimens with lower doses of total body irradiation, fractionated doses, busulfan, and malphalan than those used in myeloablative regimens are considered non-myeloablative or lower intensity conditioning regimens. The majority of BMT performed worldwide is autologous. Mobilized peripheral blood stem cells are the main graft source for autologous BMT, accounting for >90% [1]. Bone marrow is the primary graft source in children undergoing allogeneic BMT. However, the use of peripheral blood and umbilical blood grafts in children is increasing. During the period

72 72 72 72

7.10 Delayed Pulmonary Toxicity Syndrome (DPTS)..................................................................... 72 7.10.1 Clinical Findings and Diagnostic Evaluation........... 73 7.10.2 Treatment and Prognosis.......................................... 73

B. Afessa  Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA e-mail: [email protected]

73 73 73 74

69 69

7.8 Diffuse Alveolar Hemorrhage (DAH)................... 72 7.9 Periengraftment Respiratory Distress Syndrome (PERDS).................................................................. 7.9.1 Epidemiology............................................................ 7.9.2 Clinical Findings and Diagnostic Evaluation........... 7.9.3 Treatment and Prognosis..........................................

7.11 Pulmonary Cytolytic Thrombi (PCT)................... 7.11.1 Pathogenesis............................................................. 7.11.2 Clinical Findings and Diagnostic Evaluation........... 7.11.3 Treatment and Prognosis..........................................

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_7, © Springer-Verlag Berlin Heidelberg 2011

63

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B. Afessa

from 2003 to 2007, peripheral blood and umbilical cord blood grafts accounted for 28% and 20%, respectively, of allogeneic BMT in children [1]. Peripheral blood is the source of allogeneic graft in approximately 80% of BMT recipients older than 20 years. The most common indications for BMT are multiple myeloma and lymphoma, accounting for 63% in North America [1]. Multiple myeloma is the most common indication for autologous transplantation and acute myelogeneic leukemia for allogeneic transplantation. The post-transplant period is divided into three phases: pre-engraftment (0–30 days), early postengraftment (30–100 days), and late post-transplant (>100 days). BMT recipients’ underlying diseases, the chemotherapy and radiation therapy they receive to treat the underlying diseases, and the conditioning regimen result in damage to multiple organ systems. Pulmonary complications develop in 30–60% of BMT recipients [2–4]. The pulmonary complications follow characteristic time patterns [5]. With the widespread use of prophylaxis for certain infections, the spectrum of pulmonary complications following BMT has shifted from more infectious to non-infectious complications [6]. Among the non-infectious pulmonary complications, pulmonary edema, diffuse alveolar hemorrhage (DAH), and peri-engraftment respiratory distress syndrome (PERDS) usually occur during the first 30 days following transplant (Fig.  7.1). Idiopathic pneumonia syndrome (IPS) can occur at any time following transplant. We will review the main non-infectious pulmonary complications in this chapter (Tables 7.1 and 7.2).

Table  7.1  Noninfectious pulmonary complications in blood and marrow transplant recipients Isolated abnormality in pulmonary function Asthma Acute pulmonary edema Bronchiolitis obliterans Bronchiolitis obliterans organizing pneumonia Idiopathic pneumonia syndrome Diffuse alveolar hemorrhage Peri-engraftment respiratory distress syndrome Delayed pulmonary toxicity syndrome Pulmonary cytolytic thrombi Pulmonary veno-occlusive disease Progressive pulmonary fibrosis Pulmonary hypertension Hepatopulmonary syndrome Pulmonary alveolar proteinosis Eosinophilic pneumonia

7.2 Pulmonary Function Abnormalities Pulmonary function test (PFT) in BMT recipients has shown that restrictive and obstructive ventilatory defects and gas transfer abnormalities are frequent

DAH APE PERDS BOOP PCT IPS BO Acute GVHD 0

1

2

Chronic GVHD 3

4

5

6

7

8

9

10

11

12

Months Phase I

Phase II

Fig. 7.1  Timing of the major non-infectious complications following blood and marrow transplantation. BO Bron­ chiolitis obliterans, DAH diffuse alveolar hemorrhage, GVHD graft-versus-host-disease, IPS idiopathic pneumonia

Phase III

syndrome, P edema pulmonary edema, PERDS peri-engraftment respiratory distress syndrome, Phase I pre-engraftment period, Phase II early post-engraftment period, phase III late post-engraftment period

7  Noninfectious Pulmonary Involvement in Hematopoietic Stem Cell or Bone Marrow Transplant Recipients Table 7.2  Characteristics of selected pulmonary complications in BMT recipients Characteristics BO BOOP DAH

PERDS

IPS

Incidence

3.8% in allogeneic, rare in autologous

Low

5%

5%

10%

Clinical features

Dyspnea

Dyspnea

Dyspnea

Dyspnea

Cough

Cough

Cough

Cough

Fever

Dyspnea

Wheezing

Fever

Fever

Airway obstruction

↓¯ TLC

↓¯ TLC

↓¯ DLCO

↓¯ DLCO

PFT

Radiographic features

Air trapping

Consolidation

Infiltrates

Hyperinflation

Ground-glass opacity

Ground-glass opacities

Normal

Infiltrates

Diffuse infiltrates

Clinical Bronchoscopy

Bronchoscopy

65

Nodular opacity Definite diagnosis

Surgical biopsy

Surgical biopsy

Bronchoscopy

Transbronchial biopsy

Surgical biopsy

Treatment

Immunosuppressant

Steroids

Steroids

Steroids

None

Case fatality

High (59%)

Low (19%)

High (80%)

26%

74%

BMT Hematopoietic peripheral blood and bone marrow stem cell transplant, BO bronchiolitis obliterans, BOOP bronchiolitis o­ bliterans organizing pneumonia, DAH diffuse alveolar hemorrhage, DLCO diffusion of carbon monooxide, IPS idiopathic pneumonia ­syndrome, PERDS peri-engraftment respiratory distress syndrome, PFT pulmonary function test, TLC total lung capacity

long-term sequelae, particularly following allogeneic transplantation [6, 7]. A systematic review of 20 publications published between 1996 and 2001 found decreased carbon monoxide diffusion (DLCO) in 83%, restriction in 35%, and obstruction in 23% of allogeneic BMT recipients [8]. A retrospective cohort study of over 500 BMT recipients from the University of Toronto covering a more contemporary period of 1980–1997 documented somewhat lower frequencies: impaired diffusion in 35%, restriction in 12%, and obstruction in only 6% of long-term survivors [9]. While the frequency of restriction and impaired diffusion appeared constant over time, this study suggested a declining frequency of airflow obstruction: 15% in patients transplanted before 1987 compared to 5% for those receiving transplantation after 1987. The extremely low incidence of airflow obstruction documented in this study likely reflects the very stringent diagnostic criteria utilized by the authors. Utilizing a more sensitive definition, Chien and colleagues identified airflow obstruction in 26% of long-term survivors

of allogeneic BMT in a contemporary series from the Fred Hutchinson Cancer Center [10]. Notably, the development of airflow obstruction serves as a marker for increased risk of mortality following transplantation [9–11]. Risk factors for the development of PFT abnormalities following BMT include smoking history, pretransplant pulmonary infection and viral infection in the early post-transplant period, older age, underlying disease, pre-transplant chemotherapy and conditioning regimen, graft-versus-host-disease (GVHD), and HLA-mismatch [9, 10, 12–26]. Respiratory muscle weakness due to GVHD-associated myositis has been described following allogeneic BMT and may rarely be a contributing factor to restrictive pulmonary function abnormalities [27–29]. Several studies have suggested that abnormal pulmonary function may be a risk factor for the subsequent development of pulmonary complications in BMT recipients [14, 30–34]. However, some investigators have reported conflicting data showing no

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significant association between baseline pulmonary function values and subsequent pulmonary complications or mortality [15, 26]. Moreover, there is considerable variability among published studies in the particular pulmonary parameters deemed to be predictive, the post-transplant complications that they predict, and the strength of the association [35].

7.3 Asthma There are case reports of asthma developing after allogeneic BMT [36–40]. Limited data suggest that the serum IgE level, of donor origin, is elevated following transplantation [41]. Allergen-specific IgE-mediated hypersensitivity can be transferred from donor to recipient by B cells with allergen-specific memory leading to atopic dermatitis, allergic rhinitis, and asthma [36, 37, 41, 42]. The management of asthma in BMT recipients is similar to that of the other population.

B. Afessa

pulmonary complications are common in BMT recipients with GVHD. The pulmonary histology of BMT recipients with GVHD may show diffuse alveolar damage, lymphocytic bronchitis/ bronchiolitis with interstitial pneumonitis, bronchiolitis obliterans organizing pneumonia (BOOP), and bronchiolitis obliterans (BO) [45]. BO is a nonspecific inflammatory injury affecting primarily the small airways, often sparing the interstitium [46]. The term bronchiolitis obliterans has been used to describe a heterogeneous group of conditions [47]. This has been well depicted by Dr. Bergeron and colleagues in this book (see the Pearls section). In the clinical literature, it has been used to describe various conditions that result in airflow limitation. Philit et al. have recommended the term “post-transplant obstructive lung disease” instead of “bronchiolitis obliterans” because it takes into account both the functional definition and the clinical context of the syndrome [48]. Although BO can be idiopathic, it is often associated with connective tissue disease, inhaled toxins, infections, drugs, and chronic GVHD [46]. In the BMT recipient, BO is in most cases considered to be a severe manifestation of chronic GVHD, though infection and drug toxicity may be contributing factors [49].

7.4 Acute Pulmonary Edema Acute pulmonary edema in BMT recipients commonly occurs during the neutropenic phase and results from a combination of both hydrostatic and non-hydrostatic (capillary leak) factors [43]. Hydrostatic pulmonary edema may result from high volumes of fluid for medications, total parenteral nutrition, and multiple transfusions. The heart may also be compromised by a number of chemotherapeutic drugs, such as adriamycin and high-dose cyclophosphamide. Clinical features include weight gain, dyspnea, and bibasilar crackles. The radiographic findings may include vascular redistribution, increased interstitial markings, Kerley B lines, and ground-glass opacities. Cardiomegaly is generally absent unless there is associated cardiac dysfunction. Acute pulmonary edema can be prevented and treated with fluid restriction and diuretics.

7.5 Bronchiolitis Obliterans Graft-versus-host disease (GVHD) is a major complication of allogeneic BMT, with an overall incidence between 30% and 60% [44]. Infectious and non-infectious

7.5.1 Incidence and Risk Factors Airway disease as a complication of BMT was first recognized in the early 1980s [50]. BO almost exclusively affects allogeneic recipients with GVHD. There are only rare case reports of BO in autologous recipients [51]. In a study of 1,789 allogeneic BMT recipients, 47 (2.6%) developed BO compared to none of the 1,070 autologous recipients [52]. The reported incidence of BO varies among studies, related in part to patient population, and to variable definitions and diagnostic criteria. Although some studies have included pathologic findings, most of the reported cases of BO were defined by the presence of airflow limitation in the appropriate clinical setting. The frequency of BO was 3.9% among 4,180 allogeneic BMT recipients reported in 13 studies [53]. A recent study employing a highly sensitive definition of airflow obstruction documented an incidence of 26% [10]. The incidence varies between 6% and 35% in long-term survivors with GVHD [13, 49, 52, 54, 55]. GVHD, older donor and recipient age, methotrexate use, antecedent respiratory infection, and serum

7  Noninfectious Pulmonary Involvement in Hematopoietic Stem Cell or Bone Marrow Transplant Recipients

immunoglobulin deficiency are risk factors for BO [10, 13, 17, 49, 52, 56]. Patients who receive allogeneic T-cell depleted stem cells or are treated with a non-myeloablative conditioning regimen have a lower incidence of pulmonary complications, including BO [57, 58]. Although pulmonary infections are identified in many patients with BO, it is not clear whether they are directly related to airway disease or whether they result from immune suppression.

7.5.2 Pathogenesis The pathogenesis of BO in BMT recipients is not well understood. The association between BO and chronic GVHD suggests that host bronchiolar epithelial cells serve as a target for donor cytotoxic T-lymphocytes [59]. Recurrent aspiration of oral material due to esophagitis associated with GVHD, abnormal local immunoglobulin secretory function in the lungs, and unrecognized infections may also play roles [49, 59]. The variations in histopathology, bronchoalveolar lavage cellular composition, and clinical course; the frequency of associated pulmonary infection; the increased risk associated with methotrexate and the rare occurrence after autologous BMT suggest multi-factorial pathogenesis [51, 52, 59, 60].

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to exclude infection and complications of GVHD [59]. Since there is a high prevalence of sinusitis in allogeneic BMT recipients with GVHD, radiographic assessment of the paranasal sinuses is also recommended [59, 62–65]. If gastrointestinal GVHD or aspiration is a consideration, esophageal studies should be performed [59, 66]. PFT is the mainstay of diagnosis of BO [67]. Although normal airflow has been reported in BMT recipients with histologically proven BO [51], irreversible airflow obstruction is the hallmark of clinically significant disease. In lung transplant recipients, BO is classified based on spirometry into stage1 (FEV1 66–80% of peak post-transplant baseline), stage 2 (FEV1 51–65% of baseline) and stage 3 (FEV1 < 51% of baseline) [68]. The utility of this classification scheme in defining the severity or prognosis in BMT recipients has not been established. The chest radiograph is usually normal or may show hyperinflation. High-resolution computed tomography (HRCT) of the chest may show decreased lung attenuation, segmental or subsegmental bronchial dilatation, diminution of peripheral vascularity, centrilobular nodules, and expiratory air trapping (Fig. 7.2) [16, 48, 69, 70]. The most common finding on HRCT of the chest is decreased lung attenuation. The decreased lung attenuation and bronchial dilatations are more frequent and extensive in the lower lobes [69].

7.5.3 Clinical Findings and Diagnostic Evaluation BO can occur 2 months to 9 years after transplantation [17, 52, 55, 56, 61]. The majority of patients with BO present insidiously with dry cough and dyspnea, 40% develop wheezing, and 20% report antecedent “cold” symptoms; fever is notably absent [55, 56]. Twenty percent of the patients with BO had no respiratory symptoms at the time of the abnormal pulmonary function testing. Since the presenting respiratory symptoms are non-specific, a complete history, including prior medications and infections, and thorough physical examination focusing on signs of chronic GVHD should be obtained. Appropriate microbiology studies and laboratory evaluations, including complete blood count with differential, blood urea nitrogen, creatinine, total bilirubin, hepatic transaminases, gammaglobulin levels and subclasses, and urinalysis, are recommended

Fig. 7.2  Computed tomography of the chest in a patient with bronchiolitis obliterans showing diffuse areas of parenchymal hypoattenuation, proximal bronchiectasis, and subsegemental bronchial dilatation (Reprinted by permission from Afessa et al. [53], Copyright 2001 Macmillan Publishers Ltd.)

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Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is used in BMT recipients with suspected BO mainly to exclude infection as the cause of airflow obstruction. Because BO involves the respiratory and membranous bronchioles and is patchy in distribution, transbronchial lung biopsy rarely demonstrates the characteristic histological changes and is consequently of limited utility. Furthermore, transbronchial lung biopsy is contraindicated in the presence of severe airways obstruction or thrombocytopenia. BAL shows neutrophilic and/or lymphocytic inflammation, but this is a non-specific finding [60, 71]. Video-assisted thoracoscopic lung biopsy is required to make a definitive histologic diagnosis. Lung biopsies show small airway involvement with fibrinous obliteration of the lumen with or without associated interstitial pneumonia, fibrosis, or diffuse alveolar damage (Fig. 7.3) [48, 55, 72–74]. Necrotizing bronchitis and bronchiolitis have been reported [72]. The inflammatory cellular infiltrates are usually peribronchiolar and consist of neutrophils and lymphocytes in varying proportions [75]. Surgical biopsies are rarely indicated since the diagnosis usually can be made on clinical grounds. The diagnostic criteria for BO in BMT recipients have not been clearly defined. Obstructive airways disease and BO may exist as distinct clinical entities in BMT recipients. Bronchiolitis may occur without airway obstruction [59], and, conversely, airflow obstruction can occur for a number of

Fig. 7.3  Lung pathology in bronchiolitis obliterans showing bronchiolar inflammation and luminal obliteration associated with excess fibrous connective tissue. Alveoli and their ducts are spared. (Hematoxylin and eosin and Verhoeff-Van Gieson elastic tissue stain.) (Reprinted by permission from Afessa et al. [53], Copyright 2001 Macmillan Publishers Ltd.)

B. Afessa

reasons other than BO (e.g., asthma, pre-existent chronic obstructive pulmonary disease, viral bronchiolitis). BO is usually established by the presence of irreversible airflow obstruction and the exclusion of other causes of this functional abnormality. BO should be suspected in allogeneic BMT recipients, particularly those with chronic GVHD, who present with chronic cough, wheezing, dyspnea, or hypoxemia with a normal chest radiograph and no evidence of respiratory infection [53, 59]. Similarly, the diagnosis should be considered in asymptomatic patients with new onset of airflow obstruction on screening spirometry. Other chronic diseases such as pulmonary veno-occlusive disease and early diffuse interstitial disease can present with similar signs and symptoms. However, pulmonary veno-occlusive disease is rare and unlikely to show airflow obstruction. Interstitial lung disease is typically associated with a restrictive defect on pulmonary function testing and parenchymal abnormalities on HRCT of the chest.

7.5.4 Treatment The treatment of BO in the BMT recipient is empiric, and typically consists of corticosteroids and augmented immunosuppression, targeting chronic GVHD. However, only a minority of the patients shows clinical

7  Noninfectious Pulmonary Involvement in Hematopoietic Stem Cell or Bone Marrow Transplant Recipients

improvement in response to treatment [52, 53]. Prednisone in a range of 1–1.5 mg kg−1 day−1 is typically given for 4–6 weeks [59]. If the respiratory status remains stable, corticosteroid therapy is tapered and discontinued over 6–12 months. If no improvement is noted within 1 month, or if deterioration continues, cyclosporin or azathioprine can be added [59]. Antithymocyte globulin and high-dose intravenous methylprednisolone have also been used with mixed results [52]. There is a case report of an allogeneic BMT recipient with BO whose pulmonary status improved following treatment with Imatinib mesylate, a specific tyrosine kinase inhibitor with antifibrinogenic properties [76]. Macrolide antibiotics are known to have antiinflammatory properties, and have been shown to improve symptoms, lung function, and mortality in patients with panbronchiolitis [77–83]. Additionally, there are recent reports of improved lung function in lung transplant recipients with bronchiolitis obliterans syndrome who received macrolide therapy [84, 85]. Currently, there is only one published study examining the effects of macrolides in BMT recipients with BO. Khalid and colleagues reported on eight BMT recipients with BO who were given azithromycin at an initial dose of 500 mg daily for 3 days followed by 250 mg three times weekly [86]. All patients demonstrated improvement in spirometric parameters, with a mean improvement in FEV1 of 20.6% (range 7.3–42.9%). This preliminary evidence, coupled with the lack of significant adverse effects, makes macrolide therapy an attractive therapeutic option, but validation with a prospective, randomized trial is necessary before this approach can be strongly endorsed. Although there are case reports suggesting beneficial response to thalidomide in BMT recipients with BO, a recent study showed no benefit [52, 87, 88]. While hypogammaglobulinemia has been described as a risk factor for chronic GVHD, prophylaxis with intravenous immunoglobulin has not been shown to prevent BO [89]. Cyclosporin may play a protective role against BO, but its role in established BO is unproven [90]. A randomized clinical trial showed inhaled corticosteroids to be ineffective in lung transplant recipients with bronchiolitis obliterans syndrome, and there is no reason to suspect that this intervention would be any more efficacious when applied to postBMT BO [91].

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In addition to immunosuppression and anti-inflammatory therapy, adjunctive treatments are important in the management of BMT recipients with BO. Prophylaxis for Pneumocystis jiroveccii pneumonia and Streptococcus pneumoniae should be maintained. Since bacterial infections, especially sinusitis, are common in patients with BO, they should be treated aggressively. Bronchodilator therapy is recommended, although only a minority of patients responds [56, 63, 72]. In selected BMT recipients with respiratory failure secondary to BO who were deemed to be cured of the underlying malignancy for which BMT was performed, lung transplantation is an option [45, 92–95].

7.5.5 Clinical Course Serial pulmonary function tests in allogeneic BMT recipients with BO have shown that the rate of decline in FEV1 is widely variable [56]. Deterioration in FEV1 correlates with increased mortality rate [56]. The FEV1 improves in only 8–20% [55, 59, 67, 70]. The reported case fatality rates vary widely, ranging from 14% to 100%, with an average case fatality rate of 59% [96]. In one study published 2 decades ago, the 3-year mortality rate of 35 allogeneic BMT recipients with GVHD and obstructive airway disease was 65% compared to 44% for those with GVHD without obstructive airway disease [56]. In a more recent study, the 5-year survival rate of 47 BMT recipients with BO was 10% compared to 40% for those without BO, highlighting the lack of progress in the management of BO over the last 2 decades [52].

7.6 Bronchiolitis Obliterans Organizing Pneumonia (BOOP) 7.6.1 Incidence and Pathogenesis BOOP is an uncommon lung disease characterized by the presence of granulation tissue within the terminal and respiratory bronchioles, the alveolar ducts, and alveoli. It was first described as a distinct clinical entity in 1985 [97]. BOOP can be either idiopathic or

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associated with other conditions such as infections, drugs, radiation, or connective tissue diseases [98]. The first cases of BOOP in BMT recipients were reported in the early 1990s [99, 100]. BOOP is not as common as BO in BMT recipients. In a report of 296 patients with BOOP from 63 publications, BMT recipients accounted for four (1.4%) [101]. At Vancouver General Hospital, 5 of the 25 (20%) patients identified as having BOOP over an 8-year period were allogeneic BMT recipients [101]. At the author’s institution, the incidence of BOOP was 1.7% among 179 allogeneic BMT recipients who survived for 3 months or longer [70]. The published medical literature on BOOP in BMT recipients is limited to case reports, with a maximum number of five patients [45, 70, 99–107]. Idiopathic BOOP is an inflammatory lung disease of unknown etiology [98]. Its occurrence almost exclusively in allogeneic recipients with GVHD suggests that it may represent a form of alloimmune injury to the lung by the transplanted stem cell [101]. BOOP is uncommon in BMT recipients treated with T-cell lymphocyte-depleted stem cells, highlighting the role T-cell lymphocytes may play in its pathogenesis [57, 108]. The higher frequency of human leukocyte antigen (HLA) B35 in BMT recipients with BOOP, compared to those without BOOP, suggests HLA B35 may play a role in its pathogenesis [109]. The exhaled nitric oxide level is increased in allogeneic BMT recipients with BOOP [104]. The rare occurrence of BOOP in autologous recipients suggests that other mechanisms may be involved as well [102]. A case report of BOOP associated with human herpes virus-6 in a BMT recipient suggests unrecognized infections may play role [110].

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disease is usually bilateral, it can be unilateral [102]. Pulmonary function tests usually show a restrictive defect, decreased DLCO, and normal flow rates [99, 101, 104, 112]. Arterial blood gas analysis may reveal mild hypoxemia [101]. Chest radiographs and computed tomography show patchy air space consolidation, ground-glass attenuation, and nodular opacities [99–101, 104, 113, 114]. The radiographic abnormalities usually have a peripheral distribution [115]. One recent study demonstrated increased exhaled nitric oxide concentration in BMT recipients with BOOP that decreases with response to treatment [104]. Although pulmonary function test and CT scan findings in conjunction with the clinical features may suggest the diagnosis, confirmation requires either surgical or transbronchial lung biopsy. Although the diagnosis of BOOP in the BMT recipient occasionally can be made with transbronchial lung biopsy in the appropriate clinical setting, about 85% of the patients require surgical lung biopsy [101]. Histologic confirmation of the diagnosis is particularly warranted before the patient is subjected to long-term corticosteroid therapy. Surgical lung biopsy, usually via video-assisted thoracoscopy, is considered the gold standard for the diagnosis of BOOP. The histologic hallmark of BOOP is the presence of patchy intraluminal fibrosis, consisting of polypoid plugs of immature fibroblast tissue resembling granulation tissue obliterating the distal airways, alveolar ducts, and peribronchial alveolar space (Fig. 7.4) [47].

7.6.2 Clinical Presentation and Diagnostic Evaluation The onset of BOOP is usually 1 month to 2 years after transplant [70, 99–101, 103–107, 111]. The presenting symptoms of BOOP include dry cough, dyspnea, and fever. Rarely, the disease may be asymptomatic [70]. Physical examination may reveal inspiratory crackles. BOOP should be included in the differential diagnosis of airspace disease in BMT recipients not responding to antibiotics. Although the airspace

Fig. 7.4  Lung pathology in bronchiolitis obliterans organizing pneumonia showing the presence of intraluminal granulation tissue in bronchioli, alveolar ducts, and alveoli. There is also interstitial infiltration with mononuclear cells and foamy macrophages. (Hematoxylin and eosin stain.) (Reprinted by permission from Afessa et al. [53], Copyright 2001 Macmillan Publishers Ltd.)

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7.6.3 Treatment and Prognosis Corticosteroid therapy is the treatment of choice for symptomatic patients with BOOP [70, 98–101, 104]. About 80% of BMT recipients with BOOP respond favorably to treatment [70, 99–101, 103–106, 111]. The duration and dosage of corticosteroid therapy in the BMT recipient with BOOP have not been clearly defined. Based on the experience from other patients, the initial dose of prednisone is in the range of 0.75–1.5 mg kg−1 day−1 to a maximum daily dose of 100 mg, administered for 1–3 months, then 40 mg/day for 3 months, and then 10–20 mg/day or every other day for a total of 1 year [98, 116]. Radiographic abnormalities usually clear within 1–3 months of initiating corticosteroid therapy [100, 101, 104, 105]. Erythromycin 10 mg kg−1 day−1 for 14 months has been used in conjunction with corticosteroid to treat BOOP in one allogeneic BMT recipient [103]. The case fatality rate of treated BOOP is 7.9% in the general population, but appears to be higher in BMT recipients [101]. Among 27 BMT recipients with BOOP documented in the literature, the overall case fatality rate was 19% [45, 70, 99–107, 111].

7.7 Idiopathic Pneumonia Syndrome (IPS) 7.7.1 Epidemiology IPS is characterized by clinical features of pneumonia and diffuse lung injury in the absence of an identified infection. The overall frequency of IPS is 10%, with a reported range of 2–17% [53, 117, 118]. Its median time of onset is between 21 and 87 days after transplant. Risk factors for IPS include old age, transplant for malignancy other than leukemia, pre-transplant chemotherapy, total body irradiation, GVHD, and positive donor cytomegalovirus serology [53].

7.7.2 Clinical Findings and Diagnostic Evaluation IPS is defined by the presence of widespread alveolar injury in the absence of lower respiratory tract

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infection characterized by the presence of acute, bilateral pulmonary infiltrates, associated symptoms of cough and dyspnea, hypoxemia, and restrictive physiology, in the absence of infection or heart failure [119]. The pathogenesis is not well defined [120–122]. Lung tissue injury, inflammation, and cytokine release are implicated. The clinical spectrum of IPS is broad, ranging from acute respiratory failure to incidental radiographic abnormalities [119]. The usual presentations include dyspnea, dry cough, hypoxemia, and non-lobar infiltrates [119]. Because IPS mimics infectious pneumonia, the majority of the patients are on antibiotics at the time of diagnosis [123]. Infection is excluded by the absence of a pathogen in BAL fluid and by the lack of clinical response to antimicrobial therapy. Diffuse alveolar hemorrhage (DAH) and peri-engraftment respiratory syndrome (PERDS) also fulfill the diagnostic criteria of IPS [124, 125]. Despite overlap in the clinical features of IPS, DAH, and PERDS, their responses to treatment and clinical courses are different [124]. In my diagnostic approach to patients with suspected IPS, I perform BAL and, if there are no contraindications, transbronchial lung biopsy. We proceed to video-assisted thoracoscopic lung biopsy if transbronchial lung biopsy is contraindicated or if the transbronchial specimen is inadequate. Lung biopsies of patients with IPS may show diffuse alveolar damage, organizing or acute pneumonia, and interstitial lymphocytic inflammation [6, 123].

7.7.3 Treatment There have been no randomized clinical trials addressing the treatment of IPS. Despite case reports of patients with IPS responding to treatment with corticosteroids, studies with larger sample sizes have not shown any outcome benefit [6, 123, 126]. Currently, management consists of supportive care and prevention and treatment of infection. There is a report of three cases of BMT recipients with IPS whose lung function improved following the administration of etanercept [122]. This observation awaits further confirmation by an ongoing clinical trial.

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7.7.4 Clinical Course and Prognosis The clinical course of BMT recipients with IPS is usually complicated by viral and fungal infections as well as pneumothorax, pneumomediastinum, subcutaneous emphysema, pulmonary fibrosis, and auto-immune polyserositis [53]. The overall mortality of IPS is 74%, with a reported range between 60% and 86% [53]. The 1-year survival rate is less than 15% [123, 126]. For those who require mechanical ventilation, the hospital mortality exceeds 95% [123].

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usually contraindicated because of thrombocytopenia. Surgical lung biopsy is rarely necessary, but may show diffuse alveolar damage [125].

7.9.3 Treatment and Prognosis High-dose corticosteroid therapy often leads to rapid clinical improvement [125]. Unlike DAH and IPS, only about one-third of BMT recipients with PERDS require ICU admission and mechanical ventilation [125]. The reported mortality rate of PERDS is about 26% [125].

7.8 Diffuse Alveolar Hemorrhage (DAH) DAH is discussed in Chap. 3.

7.10 Delayed Pulmonary Toxicity Syndrome (DPTS)

7.9 Periengraftment Respiratory Distress Syndrome (PERDS)

Chemotherapeutic agents and radiation therapy have been associated with pulmonary toxicities that manifest weeks to years later [130, 131]. In the 1990s, many patients with breast cancer were treated with a high-dose chemotherapy regimen consisting of cyclophosphamide, cisplatin, and bischloroethylinitrosurea (BCNU), followed by autologous BMT [132]. Following transplant, a significant number of these patients developed pulmonary complications, one of the more common referred to as the delayed pulmonary toxicity syndrome (DPTS) [118, 133– 139]. DPTS develops in up to 72% of autologous BMT recipients who have received high-dose chemotherapy for breast cancer [134, 135, 140]. The relatively high frequency, low mortality, and good response to corticosteroid treatment distinguish DPTS from IPS [134, 138, 139, 141]. Because recent studies have not shown a survival benefit, the  use of autologous BMT following high-dose ­chemotherapy for breast cancer has declined [142, 143]. The pathogenesis of DPTS is not known. The depletion of reduced glutathione and impaired antioxidant defenses caused by cyclophosphamide and BCNU have been implicated [138]. One study showed no significant correlation between patient age, stage of breast cancer, chemotherapy regimen, chest wall radiotherapy, tobacco use, prior lung disease, or ­ baseline pulmonary function and the development of DPTS [140].

7.9.1 Epidemiology PERDS occurs in approximately 5% of autologous BMT recipients [125]. About one-third of DAH occurs during the peri-engraftment period, and about onethird of patients with PERDS have DAH [125, 127].

7.9.2 Clinical Findings and Diagnostic Evaluation PERDS is a subset of IPS characterized by acute lung injury during the neutrophil peri-engraftment period. It represents the pulmonary component of the engraftment syndrome, which may also present with diarrhea and skin rash [125, 128, 129]. The diagnostic criteria of PERDS include the presence of fever and evidence of pulmonary injury in the form of hypoxia (arterial oxygen saturation <90%) and/or pulmonary infiltrates on chest radiograph, in the absence of cardiac dysfunction or infection, within 5 days of neutrophil engraftment [125]. The median time to onset of PERDS is 11 days (range, 4–25 days) after transplant [125]. BAL in patients with PERDS may show neutrophilic alveolitis [125]. Transbronchial lung biopsy is

7  Noninfectious Pulmonary Involvement in Hematopoietic Stem Cell or Bone Marrow Transplant Recipients

7.10.1 Clinical Findings and Diagnostic Evaluation Patients with DPTS present with cough, dyspnea, and fever [135, 139, 140]. The onset of symptoms ranges from 2 weeks to 4 months following transplantation [139, 140]. In the context of prior breast cancer treated with high-dose chemotherapy and autologous BMT, DPTS is diagnosed by demonstration of a decline in DLCO and exclusion of infectious causes [139, 140]. The DLCO declines in over 70% of patients with breast cancer treated with high-dose chemotherapy and autologous BMT [136]. In patients with DPTS, the median absolute DLCO decrement is 26% (range, 10–73%), and a nadir is reached in 15–18 weeks following transplant [139, 140]. The most common findings on CT of the chest are groundglass opacities [139]. Other abnormalities include linear or nodular opacities and consolidation. Many patients may have a normal chest CT at the onset of DPTS [139]. Because of the typical clinical presentation and response to therapy, invasive procedures such as bronchoscopy are rarely required [134, 135, 139, 140].

7.10.2 Treatment and Prognosis Corticosteroid therapy for DPTS usually results in resolution of symptoms and improvement in DLCO without long-term pulmonary sequelae [135, 139, 140]. Treatment usually consists of prednisone initiated at a dose of 60 mg/day for 14 days and subsequently tapered over 5–7 weeks [134]. While patients are being treated with steroids, they should also receive oral trimethoprim-sulfamethoxazole or aerosolized pentamidine prophylaxis against Pneumocystis jiroveccii pneumonia [134, 140]. One case of DPTS refractory to steroid was treated successfully with interferon-gamma [144]. A study using prophylactic inhaled fluticasone propionate 880 mg every 12 h for 12 weeks starting from the day of high-dose chemotherapy demonstrated a reduction in the frequency of DPTS to 35% compared to 73% in historical controls [145]. No deaths attributable to DPTS have been reported [134, 135, 139, 140]. The 3-year survival of stage II and III breast cancer patients who developed DPTS is 84%, which is not significantly different from those of patients who did not develop DPTS [140].

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7.11 Pulmonary Cytolytic Thrombi (PCT) Pulmonary cytolytic thrombi (PCT) is a non-infectious pulmonary complication of unknown etiology. Among BMT recipients, PCT occurs exclusively after allogeneic procedures, typically in the setting of GVHD. PCT has also been described at autopsy in a non-transplant patient who died following hip replacement surgery [146]. All except 1 of the 16 BMT recipients with PCT reported in the medical literature are from a single institution [147, 148]. Fifteen of the 16 patients were under age 18 years at the time of diagnosis [147, 148]. Despite the seemingly rare and previously unrecognized nature of PCT, it was found in 15 of 33 (45%) BMT recipients who underwent surgical lung biopsy for diagnosis of pulmonary nodules at the University of Minnesota [147].

7.11.1 Pathogenesis The pathogenesis of PCT is not known. Although the hemorrhagic infarcts in PCT are similar to those seen in angioinvasive fungal infections, none of the lung biopsies in the reported PCT cases had evidence of infection [147, 148]. The development of PCT exclusively in allogeneic BMT, and chiefly in those with GVHD, suggests that it may be a manifestation of GVHD targeting the endothelium of the lungs [147]. Demonstration of clinical and radiological improvement following increased immunosuppression also favors GVHD as the underlying pathogenic mechanism [147, 148].

7.11.2 Clinical Findings and Diagnostic Evaluation Most BMT recipients with PCT have active GVHD at the time of presentation [148–150]. The onset of PCT is between 8 and 343 days (median 72) after transplantation [148–150]. All patients are febrile, and some have cough at presentation [148–150]. Dyspnea has not been reported at presentation. Chest radiographs, usually performed as part of the evaluation of persistent fever, may be normal in 25% of the patients with PCT [150]. Abnormal chest radiographic findings include nodules, interstitial prominence, and atelectasis [150]. Chest CT shows multiple

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peripheral pulmonary nodules, ranging from a few millimeters to 4 cm in size. In one study, pleural effusion was reported in 1 of 13 patients who had undergone chest CT examination [150]. Bronchoscopy with bronchoalveolar lavage is used to exclude infection. Because of the peripheral and intravascular location of the nodules in PCT, transbronchial lung biopsy is unlikely to yield a diagnosis. Histological demonstration of PCT requires surgical lung biopsy or necropsy [148, 150]. The histologic features of PCT include occlusive vascular lesions and hemorrhagic infarcts due to thrombi that consist of intensely basophilic, amorphous material that may extend into the adjacent tissue through the vascular wall [147]. The amorphous material suggests cellular breakdown products [149]. Immunohistochemical studies show a discontinuous endothelial cell layer.

7.11.3 Treatment and Prognosis Because of the unclear etiology of PCT and concerns about an infectious cause of lung nodules, patients have been treated with broad-spectrum antibiotics, antifungals, and systemic corticosteroids [150]. In one recent case report, treatment with intravenous methylprednisolone 2 mg kg−1 day−1 and cyclosporin 3 mg/kg three times daily for 1 week followed by oral prednisone 30 mg/day and 125 mg cyclosporin twice daily resulted in improvement [148]. Although it is unclear which of these various interventions is actually beneficial, most of the patients with PCT described in the literature improved clinically within 1–2 weeks and radiographically over weeks to months [150]. There has been no reported death attributed to PCT [147, 148]. Of the 15 BMT recipients with PCT reported from the University of Minnesota, 10 were still alive at an average of 13 months after diagnosis and 5 died, 1 from GVHD and 4 from infectious complications [147]. The one patient reported from Mayo Clinic died of progressive pulmonary hypertension 4 months after the diagnosis of PCT, with no evidence of PCT at autopsy [148].

7.12 Pulmonary Veno-Occlusive Disease (PVOD) PVOD is a rare cause of pulmonary hypertension that has been associated with various conditions including BMT. Pulmonary hypertension in PVOD results from

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intimal fibrosis obstructing the pulmonary veins and venules. The incidence of PVOD in BMT recipients is not known. Wingard et  al. reported PVOD in 19 of 154 autopsies of allogeneic BMT recipients (12%) [151]. However, in a recent autopsy review of 71 adult BMT recipients from the Mayo Clinic (39 allogeneic), we did not identify any case of PVOD [152]. PVOD affects both genders. There are about 28 cases of BMT recipients with PVOD in the published literature [148, 151, 153–159]. The predominant underlying disease in BMT recipients with PVOD is hematologic malignancy. However, PVOD has been found following BMT for neuroblastoma and aplastic anemia [148, 157]. Only 2 of the 28 BMT recipients with PVOD had autologous grafts [155, 157]. The frequency of PVOD is particularly high in allogeneic BMT recipients who have concurrent interstitial pneumonia and hepatic veno-occlusive disease [151]. PVOD has been reported at autopsy following resolution of PCT [148].

7.12.1 Pathogenesis Since the reported cases of BMT recipients with PVOD are limited in scope and number, its etiology is not well defined. Infection, radiation, and chemotherapy are hypothesized to be contributing factors for the development of PVOD [153–155, 157, 160–162]. BCNU, mitomycin C, and bleomycin are among the chemotherapeutic agents implicated as potential causes of vascular injury [160, 162–165].

7.12.2 Clinical Findings and Diagnostic Evaluation Presenting symptoms are non-specific and include dyspnea, lethargy, and chronic cough [162]. As the pulmonary hypertension worsens, orthopnea, cyanosis, chest pain, abdominal pain due to hepatic congestion, and exertional syncope may be noted. Physical examination is also nonspecific and may reveal bibasilar crackles and inspiratory squeaks on auscultation of the lungs and findings indicative of pulmonary hypertension including right ventricular heave, loud pulmonic heart sound, lower extremity edema, and elevated jugular venous pressure [159]. Radiographic findings include Kerley B lines, prominent central pulmonary arteries, and scattered

7  Noninfectious Pulmonary Involvement in Hematopoietic Stem Cell or Bone Marrow Transplant Recipients

patchy opacities [159, 162]. Unlike other forms of primary pulmonary hypertension, pleural effusions are common in PVOD [162]. Echocardiogram and right heart catheterization show elevated pulmonary artery pressure. Pulmonary arteriogram may show delayed runoff and venous filling without arterial filling defects [159]. PFT demonstrates a decreased DLCO and restrictive ventilatory defect [159, 162, 166]. The triad of pulmonary arterial hypertension, radiographic evidence of pulmonary edema, and normal pulmonary artery occlusion pressure suggests PVOD. However, many patients with PVOD do not have this triad, and it is often difficult to get an accurate pulmonary artery occlusion pressure tracing in these patients [162]. The diagnosis cannot be made by bronchoscopy, although the findings of hemosiderosis and sclerosed venules in transbronchial lung biopsies suggest PVOD [158]. The definitive diagnosis of PVOD requires surgical lung biopsy. In the absence of this, most cases are diagnosed at postmortem examination [151, 157]. The pathologic hallmark of PVOD is the extensive and diffuse occlusion of pulmonary veins and venules by fibrous tissue [151, 162, 167].

7.12.3 Treatment and Prognosis There is no proven therapy for PVOD. Because observational trials involving patients with primary pulmonary hypertension have suggested improved survival in those treated with anticoagulation, some advocate treating PVOD with long-term warfarin [162]. There are case reports suggesting that steroids may be beneficial in BMT recipients with PVOD [153, 159]. However, the data supporting the use of steroid therapy and anticoagulation are limited to case reports [153, 159]. In one report of two BMT recipients with PVOD, methylprednisolone 2 mg/kg daily resulted in improvement of arterial oxygenation and dyspnea within 1–2 weeks [153]. In one of these two patients, discontinuation of steroid therapy led to recurrent disease that responded to additional treatment [153]. On the other hand, there are reports of BMT recipients with PVOD who deteriorated and died despite treatment with steroid therapy [155]. The role of vasodilators in PVOD is unclear. Despite case reports of successful therapy with oral vasodilators or intravenous administration of prostacyclin in PVOD, these agents can dilate the arterial vessels without concomitant venodilation, leading to increased transcapillary

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hydrostatic pressures, acute pulmonary edema, and death [162, 168]. Lung transplantation is a consideration in patients free of other comorbidities, including the underlying condition for which BMT was performed, but there is currently no published experience on outcomes of lung transplantation in this unique setting [161, 162]. In light of the limited treatment options and the generally progressive nature of the disease, it is not surprising that most patients with PVOD die within 2 years of diagnosis [162].

7.13 Other Pulmonary Complications 7.13.1 Pulmonary Arterial Hypertension Several cases of pulmonary arterial hypertension have been reported in BMT recipients [156, 169– 171]. The pathogenesis is not clearly defined. Normal pulmonary endothelium releases vasodilators, such as prostacyclin and endothelial-derived relaxing ­factors. Radiation- and chemotherapy-associated endothelial damage may be the mechanism for the development of the pulmonary hypertension [156, 169–171]. Prostacyclin infusion and calcium channel antagonists have been used for the treatment of pulmonary arterial hypertension in BMT recipients [169–171].

7.13.2 Pulmonary Alveolar Proteinosis Pulmonary alveolar proteinosis is characterized by excessive accumulation of surfactant lipoprotein in the alveoli leading to abnormal gas exchange [172]. The diagnosis of pulmonary alveolar proteinosis is made by the presence of periodic acid Schiff proteineceaous material in bronchoalveolar fluid [173]. Cordonnier et al. described three BMT recipients with pulmonary alveolar proteinosis [173]. All three had received allogeneic transplant for leukemia between 12 and 90 days before the onset of pulmonary symptoms. Chest radiographs showed diffuse infiltrates. The clinicians had suspected infection in two and alveolar hemorrhage in one. Only one of the three survived. A very didactical case of pulmonary alveolar proteinosis is depicted in this book by Drs. Vincent and Tandjaoui (see Pearl’s section).

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7.13.3 Chronic Eosinophilic Pneumonia Three cases of chronic eosinophilic pneumonia have been reported in BMT recipients, one autologous and two allogeneic [174–176]. Despite initial response to steroid therapy, one patient had a fatal course [174].

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7  Noninfectious Pulmonary Involvement in Hematopoietic Stem Cell or Bone Marrow Transplant Recipients 98. Epler GR (2001) Bronchiolitis obliterans organizing pneumonia. Arch Intern Med 161:158–164 99. Thirman MJ, Devine SM, O’Toole K et  al (1992) Bronchiolitis obliterans organizing pneumonia as a complication of allogeneic bone marrow transplantation. Bone Marrow Transplant 10:307–311 100. Mathew P, Bozeman P, Krance RA et al (1994) Bronchiolitis obliterans organizing pneumonia (BOOP) in children after allogeneic bone marrow transplantation. Bone Marrow Transplant 13:221–223 101. Alasaly K, Muller N, Ostrow DN et al (1995) Cryptogenic organizing pneumonia. A report of 25 cases and a review of the literature. Medicine (Baltimore) 74:201–211 102. Hayes-Jordan A, Benaim E, Richardson S et  al (2002) Open lung biopsy in pediatric bone marrow transplant patients. J Pediatr Surg 37:446–452 103. Ishii T, Manabe A, Ebihara Y et al (2000) Improvement in bronchiolitis obliterans organizing pneumonia in a child after allogeneic bone marrow transplantation by a combination of oral prednisolone and low dose erythromycin [In Process Citation]. Bone Marrow Transplant 26:907–910 104. Kanamori H, Fujisawa S, Tsuburai T et al (2002) Increased exhaled nitric oxide in bronchiolitis obliterans organizing pneumonia after allogeneic bone marrow transplantation. Transplantation 74:1356–1358 105. Kanda Y, Takahashi T, Imai Y et  al (1997) Bronchiolitis obliterans organizing pneumonia after syngeneic bone marrow transplantation for acute lymphoblastic leukemia. Bone Marrow Transplant 19:1251–1253 106. Kleinau I, Perez-Canto A, Schmid HJ et  al (1997) Bronchiolitis obliterans organizing pneumonia and chronic graft-versus-host disease in a child after allogeneic bone marrow transplantation. Bone Marrow Transplant 19: 841–844 107. Przepiorka D, Abu-Elmagd K, Huaringa A et  al (1993) Bronchiolitis obliterans organizing pneumonia in a BMT patient receiving FK506 [letter; comment]. Bone Marrow Transplant 11:502 108. Huisman C, van der Straaten HM, Canninga-van Dijk MR et al (2006) Pulmonary complications after T-cell-depleted allogeneic stem cell transplantation: low incidence and strong association with acute graft-versus-host disease. Bone Marrow Transplant 38:561–566 109. Yotsumoto S, Okada F, Yotsumoto S et  al (2007) Bronchiolitis obliterans organizing pneumonia after bone marrow transplantation: association with human leukocyte antigens. J Comput Assist Tomogr 31:132–137 110. Yata K, Nakajima M, Takemoto Y et al (2002) Pneumonitis with a bronchiolitis obliterans organizing pneumonia-like shadow in a patient with human herpes virus-6 viremia after allogeneic bone marrow transplantation. Kansen­ shogaku Zasshi 76:385–390 111. Baron FA, Hermanne JP, Dowlati A et al (1998) Bronchiolitis obliterans organizing pneumonia and ulcerative colitis after allogeneic bone marrow transplantation. Bone Marrow Transplant 21:951–954 112. Epler GR (1995) Bronchiolitis obliterans organizing pneumonia. Semin Respir Infect 10:65–77 113. Muller NL, Staples CA, Miller RR (1990) Bronchiolitis obliterans organizing pneumonia: CT features in 14 patients. AJR Am J Roentgenol 154:983–987

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114. Worthy SA, Flint JD, Muller NL (1997) Pulmonary complications after bone marrow transplantation: high-resolution CT and pathologic findings. Radiographics 17:1359–1371 115. Graham NJ, Muller NL, Miller RR et al (1991) Intrathoracic complications following allogeneic bone marrow transplantation: CT findings. Radiology 181:153–156 116. Cordier JF (2000) Organising pneumonia. Thorax 55:318–328 117. Chen CS, Boeckh M, Seidel K et al (2003) Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation. Bone Marrow Transplant 32:515–522 118. Wong R, Rondon G, Saliba RM et  al (2003) Idiopathic pneumonia syndrome after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for high-risk breast cancer. Bone Marrow Transplant 31: 1157–1163 119. Clark JG, Hansen JA, Hertz MI et al (1993) NHLBI workshop summary. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis 147: 1601–1606 120. Hauber HP, Mikkila A, Erich JM et  al (2002) TNFalpha, interleukin-10 and interleukin-18 expression in cells of the bronchoalveolar lavage in patients with pulmonary complications following bone marrow or peripheral stem cell transplantation: a preliminary study. Bone Marrow Transplant 30:485–490 121. Schots R, Kaufman L, Van RI et al (2003) Proinflammatory cytokines and their role in the development of major tran­ splant-related complications in the early phase after allo­ geneic bone marrow transplantation. Leukemia 17: 1150–1156 122. Yanik G, Hellerstedt B, Custer J et  al (2002) Etanercept (Enbrel) administration for idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 8:395–400 123. Kantrow SP, Hackman RC, Boeckh M et  al (1997) Idiopathic pneumonia syndrome: changing spectrum of lung injury after marrow transplantation. Transplantation 63:1079–1086 124. Afessa B, Tefferi A, Litzow MR et al (2002) Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 166:641–645 125. Capizzi SA, Kumar S, Huneke NE et  al (2001) Periengraftment respiratory distress syndrome during autologous hematopoietic stem cell transplantation. Bone Marrow Transplant 27:1299–1303 126. Crawford SW, Hackman RC (1993) Clinical course of idiopathic pneumonia after bone marrow transplantation. Am Rev Respir Dis 147:1393–1400 127. Afessa B, Tefferi A, Litzow MR et al (2002) Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 166: 1364–1368 128. Akasheh M, Eastwood D, Vesole DH (2003) Engraftment syndrome after autologous hematopoietic stem cell transplant supported by granulocyte-colony-stimulating factor (G-CSF) versus granulocyte-macrophage colony-stimulating factor (GM-CSF). Bone Marrow Transplant 31: 113–116

80 129. Maiolino A, Biasoli I, Lima J et al (2003) Engraftment syndrome following autologous hematopoietic stem cell transplantation: definition of diagnostic criteria. Bone Marrow Transplant 31:393–397 130. Abratt RP, Morgan GW, Silvestri G et al (2004) Pulmonary complications of radiation therapy. Clin Chest Med 25: 167–177 131. Limper AH (2004) Chemotherapy-induced lung disease. Clin Chest Med 25:53–64 132. Pedrazzoli P, Ferrante P, Kulekci A et al (2003) Autologous hematopoietic stem cell transplantation for breast cancer in Europe: critical evaluation of data from the European Group for Blood and Marrow Transplantation (EBMT) Registry 1990–1999. Bone Marrow Transplant 32: 489–494 133. Bearman SI, Overmoyer BA, Bolwell BJ et al (1997) Highdose chemotherapy with autologous peripheral blood progenitor cell support for primary breast cancer in patients with 4–9 involved axillary lymph nodes. Bone Marrow Transplant 20:931–937 134. Bhalla KS, Wilczynski SW, Abushamaa AM et  al (2000) Pulmonary toxicity of induction chemotherapy prior to standard or high- dose chemotherapy with autologous hematopoietic support. Am J Respir Crit Care Med 161:17–25 135. Chap L, Shpiner R, Levine M et al (1997) Pulmonary toxicity of high-dose chemotherapy for breast cancer: a noninvasive approach to diagnosis and treatment. Bone Marrow Transplant 20:1063–1067 136. Fanfulla F, Pedrazzoli P, Da Prada GA et  al (2000) Pulmonary function and complications following chemotherapy and stem cell support in breast cancer. Eur Respir J 15:56–61 137. Jones RB, Matthes S, Shpall EJ et  al (1993) Acute lung injury following treatment with high-dose cyclophosphamide, cisplatin, and carmustine: pharmacodynamic evaluation of carmustine. J Natl Cancer Inst 85:640–647 138. Todd NW, Peters WP, Ost AH et al (1993) Pulmonary drug toxicity in patients with primary breast cancer treated with high-dose combination chemotherapy and autologous bone marrow transplantation. Am Rev Respir Dis 147: 1264–1270 139. Wilczynski SW, Erasmus JJ, Petros WP et  al (1998) Delayed pulmonary toxicity syndrome following high-dose chemotherapy and bone marrow transplantation for breast cancer. Am J Respir Crit Care Med 157:565–573 140. Cao TM, Negrin RS, Stockerl-Goldstein KE et  al (2000) Pulmonary toxicity syndrome in breast cancer patients undergoing BCNU-containing high-dose chemotherapy and autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant 6:387–394 141. Peters WP, Ross M, Vredenburgh JJ et al (1993) High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol 11: 1132–1143 142. Report on state of the art in blood and marrow transplantation. IBMTR/ABMTR Newsletter 2003; 10:7–10 143. Stadtmauer EA, O’Neill A, Goldstein LJ et  al (2000) Conventional-dose chemotherapy compared with highdose chemotherapy plus autologous hematopoietic stemcell transplantation for metastatic breast cancer. Philadelphia

B. Afessa Bone Marrow Transplant Group. N Engl J Med 342: 1069–1076 144. Suratt BT, Lynch DA, Cool CD et  al (2003) Interferongamma for delayed pulmonary toxicity syndrome resistant to steroids. Bone Marrow Transplant 31:939–941 145. McGaughey DS, Nikcevich DA, Long GD et  al (2001) Inhaled steroids as prophylaxis for delayed pulmonary toxicity syndrome in breast cancer patients undergoing highdose chemotherapy and autologous stem cell transplantation. Biol Blood Marrow Transplant 7:274–278 146. Castellano-Sanchez AA, Poppiti RJ (2001) Pulmonary cytolytic thrombi (PCT). A previously unrecognized complication of bone marrow transplantation (BMT). Am J Surg Pathol 25:829–831 147. Gulbahce HE, Pambuccian SE, Jessurun J et  al (2004) Pulmonary nodular lesions in bone marrow transplant recipients: impact of histologic diagnosis on patient management and prognosis. Am J Clin Pathol 121:205–210 148. Morales IJ, Anderson PM, Tazelaar HD et al (2003) Pulmonary cytolytic thrombi: unusual complication of hematopoietic stem cell transplantation. J Pediatr Hematol Oncol 25:89–92 149. Gulbahce HE, Manivel JC, Jessurun J (2000) Pulmonary cytolytic thrombi: a previously unrecognized complication of bone marrow transplantation. Am J Surg Pathol 24: 1147–1152 150. Woodard JP, Gulbahce E, Shreve M et al (2000) Pulmonary cytolytic thrombi: a newly recognized complication of stem cell transplantation. Bone Marrow Transplant 25:293–300 151. Wingard JR, Mellits ED, Jones RJ et al (1989) Association of hepatic veno-occlusive disease with interstitial pneumonitis in bone marrow transplant recipients. Bone Marrow Transplant 4:685–689 152. Sharma S, Nadrous HF, Peters SG et al (2005) Pulmonary complications in adult blood and marrow transplant recipients: autopsy findings. Chest 128:1385–1392 153. Hackman RC, Madtes DK, Petersen FB et  al (1989) Pulmonary venoocclusive disease following bone marrow transplantation. Transplantation 47:989–992 154. Kuga T, Kohda K, Hirayama Y et  al (1996) Pulmonary veno-occlusive disease accompanied by microangiopathic hemolytic anemia 1 year after a second bone marrow transplantation for acute lymphoblastic leukemia. Int J Hematol 64:143–150 155. Salzman D, Adkins DR, Craig F et al (1996) Malignancyassociated pulmonary veno-occlusive disease: report of a case following autologous bone marrow transplantation and review. Bone Marrow Transplant 18:755–760 156. Seguchi M, Hirabayashi N, Fujii Y et al (2000) Pulmonary hypertension associated with pulmonary occlusive vasculopathy after allogeneic bone marrow transplantation. Transplantation 69:177–179 157. Trobaugh-Lotrario AD, Greffe B, Deterding R et al (2003) Pulmonary veno-occlusive disease after autologous bone marrow transplant in a child with stage IV neuroblastoma: case report and literature review. J Pediatr Hematol Oncol 25:405–409 158. Troussard X, Bernaudin JF, Cordonnier C et  al (1984) Pulmonary veno-occlusive disease after bone marrow transplantation. Thorax 39:956–957 159. Williams LM, Fussell S, Veith RW et al (1996) Pulmonary veno-occlusive disease in an adult following bone marrow

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8

Are There Any Pulmonary Issues Specifically Related to Cord Blood Transplants? Jonathan Gutman

Contents 8.1 Introduction............................................................. 83 8.2 Infusional Toxicities................................................ 83 8.3 Preengraftment Syndrome..................................... 84 8.4 Infections................................................................. 84 8.5 Pulmonary Immune Reactions.............................. 84 References............................................................................ 84

8.1 Introduction A growing body of evidence supports the efficacy of umbilical cord blood as a donor source for hematopoietic stem cell transplantation, and the number of cord blood transplants (CBTs) is increasing [1]. Among pediatric patients, data suggest that outcomes following CBT are comparable to outcomes following unrelated donor transplants and that outcomes following well-matched CBT may be superior to outcomes following matched unrelated donor transplants. For adult patients, data continue to accumulate demonstrating outcomes similar to unrelated donor transplants, but early transplant-related mortality (TRM) due to delayed engraftment, increased graft failures, and infectious complications remains an important challenge. Broadly speaking, CBT patients can be expected to have similar pulmonary complications as non-CBT patients, and there is no significant literature des­ cribing distinct patterns of pulmonary complications ­following CBT. Given the unique immunologic characteristics of cord blood, however, larger studies may demonstrate unique pulmonary complications following CBT, and several pulmonary issues specifically related to CBT are worthy of consideration. In this brief report, we highlight complications that have been reported or that are based on our experience in recipients of CBT.

8.2 Infusional Toxicities J. Gutman  Fred Hutchinson Cancer Research Center, Seattle, Washington, USA e-mail: [email protected]

Unlike matched sibling and unrelated donor transplants, where stem cell products are typically infused fresh, cord blood units are processed, frozen, and

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_8, © Springer-Verlag Berlin Heidelberg 2011

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stored for subsequent use. Cord blood banks use a variety of strategies to process units for storage, ranging from plasma depletion only to intensive red cell depletion. Transplant centers use a variety of techniques to process frozen units prior to infusion, ranging from bedside thaw and infusion to albumin dilution and infusion to wash and infusion. In the United States, the National Marrow Donor Program (NMDP) has recently issued a warning describing four cases of serious adverse events involving heart failure and acute pulmonary edema following the use of plasmadepleted, red blood cell-replete units that were not washed prior to infusion. Based on these findings, the NMDP recommends washing of cord blood units, particularly red blood cell-replete units, prior to infusion. Physicians should be aware of this potential pulmonary/cardiovascular complication [2]. Larger studies will better characterize the incidence and pathophysiology underlying this phenomenon.

8.3 Preengraftment Syndrome Following CBT, “preengraftment” syndrome has been reported to occur at an increased frequency as compared to related or unrelated donor transplant. The syndrome is being increasingly well characterized. It develops before or at the time of engraftment, and its clinical manifestations include high fever in the absence of infection as well as diffuse erythematous skin rash resembling acute graft-versus-host disease (aGVHD) and may include fluid retention. Those patients who experience fluid retention may develop pulmonary infilitrates. The syndrome frequently responds to a brief burst of steroids (common dosing 3 days of 1 mg/kg methylpredinsolone) and appears to be distinct from early onset acute GVHD. Some data suggest, however, the preengraftment syndrome may be predictive of the subsequent development of GVHD [3].

8.4 Infections Infectious complications, including pulmonary infections, are a significant concern following CBT [4, 5]. Delayed neutrophil engraftment exposes patients to

J. Gutman

prolonged vulnerability to bacterial and fungal infections [5]. Several series have reported high rates of early TRM following CBT, and pulmonary infections account for a portion of these early events. Delayed T-cell reconstitution following CBT raises concerns about prolonged and increased risk for viral infections [6], including respiratory infections [7, 8]. No large studies, however, have quantified the incidence of respiratory viral infections following CBT. Pulmonary physicians should have a high suspicion for infectious etiologies of pulmonary symptoms ­following CBT.

8.5 Pulmonary Immune Reactions In numerous studies, cord blood is associated with a lower incidence of chronic GVHD than transplant with unrelated donors. It is reasonable to speculate, therefore, that CBT may be associated with lower ­incidences of pulmonary transplant complications attributed to immune reactions between the donor and host [9]. The incidences of bronchiolitis obliterans (BO) and bronchiolitis obliterans organizing pneumonia (BOOP) may be lower following CBT [10, 11], but no studies to date have examined this outcome. In conclusion, although there is no sound evidence of increased incidence of respiratory events in recipients of CBTs, clinicians must be aware of some infectious or noninfectious conditions that may occur in CBT patients. Given the unique immunologic characteristics of cord blood, several pulmonary issues ­specifically related to CBT (infusional toxicity, preengraftment syndrome, pulmonary infections, and ­pulmonary immune reactions) are worthy of consideration.

References   1. Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A, Jacobsen N, Ruutu T, De Lima M, Finke J, Frassoni F, Gluckman E, Acute Leukemia Working Party of European Blood and Marrow Transplant Group, Eurocord-Netcord Registry (2004) Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med 351(22):2276–2285, 25 Nov 2004

8  Are There Any Pulmonary Issues Specifically Related to Cord Blood Transplants?   2. Konuma T, Ooi J, Takahashi S, Tomonari A, Tsukada N, Kobayashi T, Sato A, Kato S, Kasahara S, Ebihara Y, Nagamura-Inoue T, Tsuji K, Tojo A, Asano S (2008) Cardiovascular toxicity of cryopreserved cord blood cell infusion. Bone Marrow Transplant 41(10):861–865   3. Patel KJ, Rice RD, Hawke R, Abboud M, Heller G, Scaradavou A, Young JW, Barker JN (2010) Pre-engraftment syndrome after double-unit cord blood transplantation: a distinct syndrome not associated with acute graft-versushost disease. Biol Blood Marrow Transplant 16(3):435–440   4. Cahu X, Rialland F, Touzeau C, Chevallier P, Guillaume T, Delaunay J, Ayari S, Dubruille V, Le Gouill S, Mahe B, Gastinne T, Blin N, Saulquin B, Harousseau JL, Moreau P, Mohty M (2009) Infectious complications after unrelated umbilical cord blood transplantation in adult patients with hematologic malignancies. Biol Blood Marrow Transplant 15(12):1531–1537   5. Szabolcs P, Cairo MS (2010) Unrelated umbilical cord blood transplantation and immune reconstitution. Semin Hematol 47(1):22–36   6. Montesinos P, Sanz J, Cantero S, Lorenzo I, Martín G, Saavedra S, Palau J, Romero M, Montava A, Senent L, Martínez J, Jarque I, Salavert M, Córdoba J, Gómez L, Weiss S, Moscardó F, De la Rubia J, Larrea L, Sanz MA, Sanz GF (2009) Incidence, risk factors, and outcome of cytomegalovirus infection and disease in patients receiving prophylaxis with oral valganciclovir or intravenous ganciclovir after umbilical cord blood transplantation. Biol Blood Marrow Transplant 15(6):730–740, Epub 2009, Apr 11

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  7. Almyroudis NG, Fabian J, Hahn T, Segal BH, Wetzler M, McCarthy PL Jr (2009) Late infectious complications after cord blood stem cell transplantation. Eur J Clin Microbiol Infect Dis 28(11):1405–1408   8. Yazaki M, Atsuta Y, Kato K, Kato S, Taniguchi S, Takahashi S, Ogawa H, Kouzai Y, Kobayashi T, Inoue M, Kobayashi R, Nagamura-Inoue T, Azuma H, Takanashi M, Kai S, Nakabayashi M, Saito H, Japan Cord Blood Bank Network (2009) Incidence and risk factors of early bacterial infections after unrelated cord blood transplantation. Biol Blood Marrow Transplant 15(4):439–446   9. Shima T, Yoshimoto G, Miyamoto T, Yoshida S, Kamezaki K, Takenaka K, Iwasaki H, Harada N, Nagafuji K, Teshima T, Shimono N, Akashi K (2009) Disseminated tuberculosis following second unrelated cord blood transplantation for acute myelogenous leukemia. Transpl Infect Dis 11(1): 75–77 10. Gutman JA, Leisenring W, Appelbaum FR, Woolfrey AE, Delaney C (2009) Low relapse without excessive transplantrelated mortality following myeloablative cord blood transplantation for acute leukemia in complete remission: a matched cohort analysis. Biol Blood Marrow Transplant 15(9):1122–1129 11. Majhail NS, Parks K, Defor TE, Weisdorf DJ (2006) Diffuse alveolar hemorrhage and infection-associated alveolar hemorrhage following hematopoietic stem cell transplantation: related and high-risk clinical syndromes. Biol Blood Marrow Transplant 12(10):1038–1046

 

9

Cardiovascular Complications of Cancer Therapeutics Aarif Y. Khakoo and Callie S. Kwartler

Contents 9.1 Introduction............................................................. 87 9.2 Anthracyclines........................................................ 9.2.1 Genetic Risk............................................................. 9.2.2 Mechanistic Insights................................................. 9.2.3 Synergistic Interactions............................................ 9.2.4 Cardioprotective Strategies....................................... 9.2.5 Conclusions..............................................................

90 91 91 92 93 95

9.3 Mitoxantrone........................................................... 95 9.3.1 Mechanistic Insights................................................. 95 9.4 Tyrosine Kinase Inhibitors.................................... 96 9.4.1 Trastuzumab.............................................................. 96 9.4.2 Lapatinib................................................................... 97 9.4.3 Imatinib..................................................................... 97 9.4.4 Dasatinib and Nilotinib............................................. 98 9.4.5 Sunitinib.................................................................... 98 9.4.6 Sorafenib................................................................... 99 9.4.7 Bevacizumab............................................................. 99 9.4.8 Conclusions.............................................................. 100 9.5 Monoclonal Antibody Therapies........................... 100 9.5.1 Alemtuzumab............................................................ 100 9.5.2 Rituximab................................................................. 100 9.5.3 Cetuximab................................................................. 101

9.9 Other Chemotherapeutic Agents.......................... 102 9.9.1 Bleomycin................................................................. 102 9.9.2 Irinotecan.................................................................. 103 9.9.3 Cytarabine................................................................. 103 9.9.4 Gemcitabine.............................................................. 103 9.10 Microtubule-Altering Therapies........................... 103 9.10.1 Vinca Alkaloids........................................................ 103 9.10.2 Taxanes..................................................................... 104 9.11 Hormone Therapies................................................ 104 9.12 Other Miscellaneous Drugs.................................... 104 9.12.1 Bortezomib............................................................... 104 9.12.2 Thalidomide.............................................................. 105 9.12.3 Interferon-a.............................................................. 105 9.12.4 Arsenic Trioxide....................................................... 106 9.12.5 IL-2........................................................................... 106 9.13 Cardiotoxicity as a Discovery Platform................ 106 9.14 Conclusion............................................................... 107 References............................................................................ 108

9.1 Introduction

9.6 5-Fluorouracil and Capecitabine........................... 101 9.7 Cyclophosphamide.................................................. 101 9.8 Cisplatin and Cisplatin-Based Combination Therapies................................................................. 102 9.8.1 Toxicity with Combination Therapies...................... 102

A.Y. Khakoo () Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030 e-mail: [email protected] C.S. Kwartler Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX, 77030

As treatment for cancer has modernized and the number of anticancer drugs has multiplied, survival of cancer patients beyond their initial disease has improved dramatically. Perversely, the same agents that bring about a “cure” for cancer can also lead to devastating cardiovascular side effects, including cardiomyopathy, myocardial infarction, thromboembolism, hypertension, arrhythmias, and QT prolongation. In fact, cancer survivors are in many cases more likely to develop cardiovascular disease than experience a recurrence of their malignancy. Cardiovascular toxicities not only increase morbidity and mortality for these patients, but also impair the ability of clinicians to manage a patient’s anticancer regimen with maximal efficiency. This chapter provides

É. Azoulay (ed.), Pulmonary Involvement in Patients with Hematological Malignancies, DOI: 10.1007/978-3-642-15742-4_9, © Springer-Verlag Berlin Heidelberg 2011

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A.Y. Khakoo and C.S. Kwartler

Table 9.1  Cardiotoxic drugs by disease presentation Cardiomyopathy Drug Incidence

Notes

Anthracyclines (chronic)

4–26% [3, 6]

Symptomatic dilated cardiomyopathy or heart failure; irreversible

Mitoxantrone (chronic)

2.6% [54, 55]

Symptomatic heart failure; irreversible

Trastuzumab

1–10% [26, 63–65]

LV dysfunction in up to 10%, heart failure in 1–4%; reversible

Lapatinib

0.2–2% [66, 72]

LV dysfunction in 2%, symptomatic heart failure in 0.2%; reversible

Imatinib

1.7–4% [191, 192]

Symptomatic heart failure

Sunitinib

11–19% [86, 87]

LV dysfunction in 19%, grade 3 dysfunction or clinical heart failure in 7%

Cyclophosphamide

10–28% [110, 193]

Typically acute onset within 1–10 days of first dose

Mitomycin

Rare [54, 194]

Interferon a

Unknown [88]

Dilated cardiomyopathy; incidence suspected to be underreported due to similar symptoms with other complications

Gemcitabine

1.8% [136]

Cardiac dysfunction with decline in LVEF

Bortezomib

Up to 10% [163, 195]

Mostly based on case reports and one study that found a 10% incidence of heart failure serious enough to cause hospitalization

All-trans retinoic acid

17% [194]

Described as “substantial decline” in LVEF, symptomatic of “retinoic acid syndrome”

Thromboembolism Alemtuzumab

Rare [101, 196]

Controversial; events observed in some studies but not others

Cisplatin

Up to 12.9% [119, 120]

Includes DVT, PE, arterial thromboses, CVA, and angina pectoris; high risk of grade 4 or 5 events

Irinotecan

Up to 20% [131]

Both venous and arterial thromboembolic events

Oxaliplatin

1–2% [5]

Increased incidence (8%) when combined with capecitabine

Estramustine

Up to 10% [54]

Includes coronary ischemia, cerebrovascular ischemia, PE, and venous thromboembolism

Tamoxifen

1.2% [156, 197]

Includes DVT and PE

Thalidomide

12–20% [95, 167]

Includes lower extremity DVT and PE most commonly, but rarely stroke, unstable angina, and cerebral venous sinus thrombosis reported

Denileukin diftitox

11% [194]

Results from vascular leak syndrome

Bevacizumab

2–11% [5, 96, 97]

mostly arterial thromboembolism; includes CVA, angina, sudden death, and other manifestations

Sunitinib

17–47% [86, 198]

Any grade 47%, grade 3 or higher 17%

Sorafenib

“Common” [91]

Mechanistically similar to sunitinib, so incidence is likely similar

Bevacizumab

8–18% [96]

Grade 3 or higher hypertension 8–18%

Hypertension

9  Cardiovascular Complications of Cancer Therapeutics Table 9.1  (continued) Hypertension Drug

89

Incidence

Notes

Vinorelbine

Rare [145]

Based on case reports

Docetaxel

Unknown [5]

Can cause either hypo- or hypertension

Dasatinib

1% [78, 199]

Grade 3–4 QT prolongation

Nilotinib

3% [77–79]

Grade 3–4 QT prolongation

Arsenic trioxide

Up to 63% [169–172]

Can lead to tachyarrhythmias, torsades de pointes, or sudden death

Vorinostat

3.5–6% [194]

QT prolongation

Myocardial infarction Gefitinib

Rare [200]

Case reports only

Sorafenib

2.9% [92, 93]

Acute coronary symptoms including MI

Cisplatin

12.9% [116–118]

Ischemic disease; more common in elderly; possibly related to thromboembolic disease (see above)

Bleomycin

<3% [130]

Severe chest pain; rare ischemia or MI in young patients

Etoposide

Rare [194, 201]

Case reports only; rechallenge worsens cardiac function

Gemcitabine

Rare [137, 138]

Case reports only

Vinca alkaloids

1% [54, 144, 145]

5-Fluorouracil

4% [106]

Myocardial ischemia or infarction, likely due to coronary vasospasm

Capecitabine

<4% [108]

Similar to 5-fluorouracil

Aromatase inhibitors

1–2% [155, 202, 203]

Increased incidence relative to tamoxifen, but controversial as to whether incidence is increased relative to controls

IL2

More than 1.5% [176]

1.5% treatment-related deaths; MI and ischemia are more common

Pentostatin

Rare [194]

Case reports only; incidence increases when co-treated with cyclophosphamide

Methotrexate

Rare [54]

Case reports only

Anthracyclines (acute)

Rare [1, 5]

Transient ventricular arrhythmias

Mitoxantrone (acute)

Rare [54, 55]

Transient ventricular arrhythmias

Nilotinib

2% [79]

Alemtuzumab

Rare [101, 196]

Controversial; events observed in some studies but not in others

Rituximab

1–7% [204]

Various types of arrhythmias

Gemcitabine

2–3% [136, 139, 140]

Case reports of atrial fibrillation; grade 1–4 ventricular tachyarrhythmias in 2.3%

5-fluorouracil

>2.2% [105]

2.2% suffer cardiac death due to arrhythmias

Arrhythmias

(continued)

90 Table 9.1  (continued) Arrhythmias Drug

A.Y. Khakoo and C.S. Kwartler

Incidence

Notes

Paclitaxel

5% [146, 151]

Sinus bradycardia in up to 30%, more serious arrhythmias in 5%; typically transient

Docetaxel

Up to 5% [5]

Dysrhythmias or tachycardia

Bortezomib

Rare [163, 195]

Mostly case reports

Interferon a

Up to 20% [54, 168]

Supraventricular arrhythmias most common; can be lethal

IL-2

6% [54]

Homoharringtonine

Rare [194]

Most common presentation is hypotension; arrhythmias are rare

Pentostatin

Rare [194]

Case reports only; incidence increases when co-treated with cyclophosphamide

Methotrexate

Rare [54, 205]

Case reports only, no typical clinical presentation of arrhythmia

LV left ventricular, LVEF left ventricular ejection fraction, DVT deep venous thrombosis, PE pulmonary embolism, CVA cerebrovascular accident, MI myocardial infarction

an overview of the cardiovascular complications associated with specific anticancer drugs (see Table 9.1 for a list of effects categorized by disease presentation). We specifically focus on the drugs most strongly associated with cardiotoxicities, and present information on the risk factors, incidence, and specific mechanisms of the effect on the cardiovascular system.

9.2 Anthracyclines Anthracyclines are a class of drugs originally isolated from microorganisms that are used to treat a wide spectrum of cancers. Doxorubicin (also called adriamycin) and daunorubicin were the original anthracyclines, and are still the most potent antitumor drugs in the class [1]. Epirubicin, idarubicin, and others have since been developed in attempts to create a better anthracycline with more potent antitumor effects and less cardiotoxicity. Daunorubicin and idarubicin are typically used to treat acute lymphoblastic and myeloblastic leukemias, while doxorubicin and epirubicin are used to treat a broader spectrum of solid and hematological cancers [2]. The antitumor effects of anthracyclines are mediated by their DNA intercalating effects and inhibition of topoisomerase II [3]. The potency of the antitumor effect, however, is counterbalanced by a severe dose-

dependent toxic effect causing irreversible cardiomyopathy. However, cardiotoxicity may not be mediated through the same mechanisms as antineoplastic effects, and appears to be independent of tumor type [4]. There are four general categories of cardiotoxicity related to anthracyclines: acute (during or immediately after treatment), subchronic (within 1–3  days after treatment), early chronic (develops late in the treatment course or up to months after completion of treatment), and delayed or late-onset (manifests years to decades after therapy). Acute cardiotoxicity, which is not dosedependent, most frequently manifests as transient arrhythmias [5]. In rare cases, however, acute doxorubicin toxicity has been shown to cause acute heart failure with a decrease in left ventricular ejection fraction down to 10%. By contrast, subchronic cardiotoxicity is most frequently seen as a pericarditis-myocarditis syndrome, and the chronic and late-onset cardiotoxicities are usually characterized by dilated cardiomyopathy, which results in a decline in systolic or diastolic cardiac function and eventually congestive heart failure [6]. Delayed cardiotoxicity most frequently manifests in survivors of childhood cancer and can be particularly brought to the surface by stressors such as pregnancy. Risk factors contributing to the incidence of anthracycline cardiotoxicity include the extremes of age, preexisting cardiac disease, female gender, AfricanAmerican race, and trisomy 21. Use of certain other

9  Cardiovascular Complications of Cancer Therapeutics

chemotherapeutic agents or mediastinal radiation along with anthracyclines also increases risk [7]. These risk factors apply to both acute and all chronic types of cardiotoxicity [8]. However, the most significant (and in some studies the only independent) ­predictor of developing anthracycline-induced cardiomyopathy is cumulative dose. Dosing limits have been set for each drug above which the incidence of cardiotoxicity becomes unacceptably high: for doxorubicin dose is limited to 400–450  mg/m2, whereas for the modified anthracycline epirubicin the limiting dose is 750  mg/m2[5]. Even at these confined doses, reports cite incidences of chronic cardiotoxicity ranging from <4% to 26%. Studies have suggested that children respond differently to anthracyclines than adults, with possibly less risk of developing acute or chronic cardiomyopathy but significantly increasing risk with time from treatment of developing delayed cardiomyopathy. Indeed, one clinical trial that looked at 607 children found a cumulative incidence of anthracycline-induced heart failure of 2.8% 6.3 years after treatment, but that risk increased significantly up to 5% after 15 years of follow-up [9]. Longer follow-up times would likely yield even higher incidences of cardiac dysfunction in childhood cancer survivors treated with anthracyclines [4]. The cumulative dose above which incidence was significantly increased was also lower in children: only 300 mg/m2 of doxorubicin [8].

9.2.1 Genetic Risk Some recent work has shown that genetic factors influence the development of anthracycline cardiotoxicity. Strong support for a genetic role in determining risk originally came from knockout and transgenic animal studies that showed increased sensitivity or resistance to anthracyclines. For example, overexpression of the multi-drug resistance gene MDR1 is protective, while overexpression of the carbonyl reductase gene is sensitizing. In humans [10], higher incidences of anthracycline cardiotoxicity have been found associated not only with SNPs in NADPH oxidase, but also with polymorphisms in GSTP, a phase II detox enzyme, and CBR3, a paralog of the carbonyl reductase CBR1 [11]. One group sequenced candidate

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genes in patients who did or did not develop cardiotoxic responses to anthracycline therapy. They found significantly associated SNPs in multiple NADPH oxidase subunits, suggesting the importance of this protein complex in modulating risk of anthracycline cardiotoxicity. They also found that SNPs in three transmembrane efflux receptors responsible for transport of anthracyclines correlated strongly with acute cardiotoxic responses. Polymorphisms in adrenergic receptors and angiotensin-converting enzymes were not associated with increased cardiotoxicity [10]. With the sequencing of the human genome and the development of more advanced methods for genomewide association studies, continued research into this area could be crucial both to understanding the mechanisms and to predicting risk of individual patients. In the future, patients with alleles increasing their risk could be put on lower doses of anthracyclines or be treated with alternative drugs to decrease the overall incidence of cardiotoxicity substantially.

9.2.2 Mechanistic Insights Recent focus has been on determining mechanisms of cardiotoxicity in the hope of identifying possible cardioprotective mechanisms or deriving a new anthracycline that is less cardiotoxic but no less potent against tumors. Endomyocardial biopsies of affected hearts reveal characteristic ultrastructural features of anthracycline-induced cardiac damage. Cytoplasmic vacuolization, swelling of mitochondria, increased numbers of lysosomes, loss of myofibrils, and dilation of the sarcoplasmic reticulum are all frequently observed changes [12]. Treatment of cultured cardiomyocytes with anthracyclines induces an apoptosis-like cell death phenotype similar to that observed in the tissue [13]. Interference with multiple aspects of cardiomyocyte cellular function have been observed after exposure to anthracyclines, including effects on myocardial calcium handling [14], adrenergic receptor signaling [14], myocardial protein synthesis [15], and mitochondrial function [16]. In addition, multiple studies have demonstrated that anthracyclines induce cardiomyocyte myofibrillar disarray [17] and apoptosis [12]. While it is difficult to completely unify these diverse

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cytotoxic effects to one mechanism of cellular injury, many studies have suggested a central role of oxidative stress, leading to increased reactive oxygen species, lipid peroxidation, and iron-regulated oxidative damage. Such studies have provided the mechanistic basis for cardioprotective strategies (discussed below), which have had mixed results in the clinical setting. Over the past 2 decades data have emerged to suggest that alternative mechanisms independent of ROSmediated damage are important in anthracyclineinduced cardiotoxicity [1]. Such alternative mechanisms may be better targets for more effective cardioprotective strategies. One such alternative theory proposes that oxidative stress (mediated by the formation of ROS by redox cycling of anthracyclines) plays a primary role only in the development of acute anthracycline cardiotoxicity, while secondary alcohol metabolites of anthracyclines accumulate in cardiac tissue over time and lead to chronic cardiotoxicity [2]. Anthracycline molecules bear a quinone moiety that can be reduced by two electrons to form secondary alcohol metabolites such as doxorubicinol [18]. Such metabolites potently impair cardiomyocyte calcium handling to a much greater degree than their parent compounds through effects on calcium handling proteins [19] and on sarcoplasmic reticulum Ca2+-induced Ca2+ release [20] in a free-radical independent manner.

9.2.3 Synergistic Interactions Anticancer agents that are commonly co-administered with anthracyclines or commonly administered in patients previously treated with anthracyclines may enhance cardiac toxicity of anthracyclines, despite the fact that such agents alone exhibit minimal cardiac toxicity. One such class of drugs is the taxanes, which are microtubule-stabilizing drugs that inhibit tumor growth by causing cell-cycle arrest. Paclitaxel and docetaxel, both widely used taxanes, have both been shown to increase formation of doxorubicinol, the secondary alcohol metabolite of doxorubicin. Kinetic studies showed that at low doses (such as those given to patients), taxanes bind with high affinity to a regulatory or allosteric site of the aldehyde reductase enzymes

A.Y. Khakoo and C.S. Kwartler

that convert anthracyclines to their metabolites. However, at high doses taxanes begin to compete with anthracyclines to bind to the active sites of these enzymes and thus prevent alcohol formation [21]. Clinically, initial studies demonstrated an enhancement of anthracycline-induced cardiac toxicity occurring when co-administered with paclitaxel; [22] however, subsequent adjusted dosing regimens have minimized this effect [23]. The use of docetaxel simultaneously with doxorubicin does not appear to enhance the rates of clinically significant cardiac toxicity compared with anthracyclines administered as a single agent [23]. Co-administration of anthracyclines and the antiErbB2 antibody trastuzumab results in a high rate of heart failure. Up to 28% of patients treated with this regimen experienced a cardiac event [24, 25] with 15% experiencing a grade 3 or 4 complication [26]. One hypothesis to explain this synergistic relationship is that trastuzumab alters ErbB2 signaling to interfere with the regulation of cytoskeletal proteins, while anthracyclines directly affect biosynthesis of sarcomeric proteins. These two independent mechanisms both leading to an effective contractile dysfunction could be causing the additive effect of cardiotoxicity [27]. More frequently cited, however, is the “multiple hit” hypothesis: that anthracyclines induce oxidative stress, and myocytes typically signal through survival pathways like ErbB2 in response to that stress. In fact, data in anthracycline-treated patients suggest that ErbB2-dependent signaling in the myocardium may be particularly important in the setting of anthracycline treatment. Myocardial uptake of indium-labeled trastuzumab was seen in 50% of patients within 3 weeks after anthracycline treatment, while only 9% of patients exhibit myocardial uptake of labeled trastuzumab 11 months after anthracyline administration, and no uptake is detected in the hearts of patients with heart failure not due to anthracyclines [28]. It is essential to be wary of combining new drugs with anthracyclines, as these examples show. Another study on pharmacokinetics of doxorubicin showed that even drugs that do not react with the quinone moiety to increase ROS formation or with the reductase enzymes to speed secondary alcohol metabolite formation can still cause increased cardiotoxicity by competing

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sterically for anthracycline-degrading factors like MbIV-O. Even drugs with no cardiotoxic effects themselves could interfere with doxorubicin metabolism in this way [29].

9.2.4 Cardioprotective Strategies Since anthracycline-induced cardiotoxicity is irreversible and usually unresponsive to traditional heart failure treatments like digitalis, ACE inhibitors, and beta-blockers,

several strategies have been developed to reduce the risk of heart failure due to anthracyclines. Table 9.2 summarizes the results of several strategies to reduce the risk of cardiotoxicity resulting from anthracyclines. Continuous infusion of anthracycline as opposed to standard, bolus therapy showed initial promise as a cardioprotective strategy [30]. Enthusiasm for this approach was tempered by other reports that were unable to reproduce this cardioprotective effect [31]. Thus, there remains a wide spectrum of administration protocols for anthracycline infusion at different centers, with continuous infusion reserved for patients at high risk for cardiotoxicity.

Table 9.2  Cardioprotective strategies for anthracyclines Strategy

Doxil (Pegylated Lipoxomal Doxorubicin) [34, 35, 206, 207]

Slow infusion (>6 hours) [30, 31, 208]

Dexrazoxane[40]

ACE inhibitors [46, 209]

Beta blockers [45, 209]

Net decrease of Cardiotoxicity

RR= 0.38 for heart failure combined

RR = 0.27 for clinical heart failure, also protective against subclinical disease

RR = 0.29 for heart failure combined

Significant increase in average LVEF after treatment

Significant increase in avg LVEF after treatment

Effect on Cancer therapy efficacy

RR = 1.01 for tumor response, 1.01 for progression free survival

RR = 1.2 for tumor response, 1.42 for overall survival (difference  not statistically significant)

RR = 0.89 for tumor response, 1.01 for progression-free survival

None reported

None reported

Adverse effects

increased skin toxicity (PPE), bone marrow toxicity, and infusion reactionsp; decreased alopecia, myelosuppression, mucositis

Decreased gastrointestinal effects, no effect on myelosuppression or alopecia

No change in thrombocytopenia, neutropenia, slight increase in abnormal white blood cell count  and anemia (RR=1.19); increased pain on injection; increased phlebitis and fever; decreased stomatitis, nausea/vomiting; one studied suggested high risk of secondary malignant disease

Incraesed incidence of dizziness, hypotension, and fatigue Fetal kidney damage if taken during pregnancy

None specifically reported Beta-blockers can increase risk of hypoglycemic shock in diabetic patients, and can reduce circulation to extremitie, dizziness and clinical depression are also common

Other notes

Doxil formulation has greatly increased half-life and higher uptake in tumor cells

This strategy is used routinely at MD Anderson Cancer Center; some evidence suggests it is not effective in children

Dexrazoxane is the only co-drug that has been proven to be cardioprotective by several rigorous clinical trials

ACE is are also used to slow progression of cardiomyopathy once it occurs

Beta-blockers are also used to slow progression of cardiomyopathy once it occurs

RR risk ratio (<0.5 is significantly beneficial, >2 is significantly harmful)

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Changes in the chemical structure or method of formulation of anthracyclines have also been devised in an effort to reduce cardiotoxicity without reducing tumor efficacy. Epirubicin is a structurally modified analog of doxorubicin, which has less toxicity on an equimolar basis [32], but comparative studies have not detected a significant difference in cardiotoxicity between these two drugs when used at dosages that are efficacious in cancer therapy [33]. Pre-clinical studies strongly suggest that epirubicin is converted to its secondary alcohol metabolite epirubicnol at a much lower efficiency than conversion of doxorubicin to doxorubicinol [2]. Thus, one would predict that epirubicin would have significantly lower incidence of chronic cardiac toxicity compared with doxorubicin when used at dosages with equivalent anticancer efficacy, but this has not yet been clearly demonstrated in head-to-head clinical trials. Furthermore, a meta-analysis of five randomized, controlled trials found no significant difference between rates of cardiotoxicity associated with epirubicin compared with that of doxorubicin [34]. More favorable findings have been demonstrated with the use of liposomal anthracycline formulations, particularly with pegylated liposomal doxorubicin (PLD, Doxil) [35, 36]. In a large phase III trial of patients with metastatic breast cancer that compared conventional doxorubicin and PLD, the latter was associated with a highly significant (P < 0.0001), threefold decreased risk in cardiotoxicity, with no difference in antitumor efficacy [35, 36]. The EDTA-like iron chelator dexrazoxane has also shown promise in preventing anthracycline-induced cardiotoxicity. Dexrazoxane was originally itself an anticancer drug whose cardioprotective effects were discovered accidentally [3]. Treatment of cultured cardiomyocytes with doxorubicin causes loss of mitochondrial DNA and cell death, pre- or co-treatment with dexrazoxane significantly reduces these effects [37]. Dexrazoxane has two mechanisms of action: in tumor cells it, like anthracyclines, is a strong inhibitor of topoisomerase II. In cardiomyocytes, meanwhile, it is metabolized to an EDTA-type form that chelates iron and prevents oxidative damage to the cells [38]. In one of the first randomized trials of this agent, patients treated with dexrazoxane had significant decreases in the incidence of cardiotoxicity caused by doxorubicin as determined by the development of congestive heart failure (CHF) left ventricular dysfunction (LVD) and changes on endomyocardial biopsy

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consistent with anthracycline cardiotoxicity [39]. A meta-analysis of six randomized, controlled trials concluded that ­dexrazoxane significantly reduces the incidence of anthracycline-induced heart failure [relative risk (RR) = 0.28, CI 0.18–0.42, P < 0.000001] [40]. This same meta-analysis identified a trend towards decreased tumor response in patients receiving dexrazoxane (RR = 0.88, CI 0.77–1.01, P = 0.06), although a significant worsening in tumor response rate in patients treated with dexrzoxane has only been observed in one study [41]. Notably, although dexrazoxane can worsen both thrombocytopenia and granulocytopenia during cancer therapy, no significant difference in the incidence of these adverse effects was identified in the meta-analysis. Furthermore, an overall survival benefit has not been observed in patients receiving dexrazoxane for cardioprotection in either a large randomized trial [41] or in the meta-analysis of six randomized studies [40]. For all of these reasons, the usage of dexrazoxane is limited to subsets of pediatric patients and patients at high-risk of cardiotoxicity due to anthracyclines, such as those with pre-existing cardiac disease. The nonspecific beta-blocker carvedilol, a mainstay of therapy for patients with heart failure, has potent antioxidant and antiapoptotic properties, which suggest that it may be effective as a protective agent for anthracycline-induced cardiotoxicity [42]. Preclinical studies have demonstrated that carvedilol protects cardiomyocytes from anthracycline-induced damage in vitro [43] and in animal model studies [44]. A recent small, placebo-controlled study demonstrated a similar cardioprotective effect of once-daily carvedilol in patients receiving anthracycline-based chemotherapy [45]. Larger, randomized clinical studies are needed to confirm the utility of carvedilol as a cardioprotective agent for patients receiving anthracycline-based chemotherapy. A recent report integrating the use of cardiac biomarkers with the use of the angiotensin-converting enzyme (ACE) inhibitors as a chemoprotective strategy demonstrated a promising approach [46]. In a randomized study of patients who received high-dose chemotherapy with elevated serum troponin I levels, none of the 56 patients randomized to receive enalapril developed heart failure, while 14 of 58 (24%) control patients developed heart failure. This finding was consistent with pre-clinical observations demonstrating that ACEinhibitors provide a powerful cardioprotective effect in animals receiving anthracyclines [47, 48]. While we

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await further large trials of these chemoprotection strategies, it is reasonable to use ACE-inhibitors prophylactically in patients receiving anthracyclines who have a high-risk of developing cardiotoxicity or in whom antihypertensive therapy is indicated. This approach is in accordance with the recently updated American Heart Association/American College of Cardiology guidelines for the treatment of heart failure [49]. Many other molecules and drugs have been tested as potential cardioprotective agents, with several showing promise in cell culture or animal studies. For example, probucol is an antioxidant with lipid-lowering effects, and has been shown to effect doxorubicin pharmacokinetics without affecting antitumor efficacy. Pretreatment with probucol significantly decreases doxorubicin concentrations in plasma and also reduces markers of cardiac damage in pre-clinical studies [12, 50]. Two hypotheses about its mechanism have been proposed: either probucol could inhibit conversion of doxorubicin into its toxic secondary alcohol metabolite doxorubicinol or its effect may be to accelerate excretion of the drug through the kidney through an antioxidant effect, thus reducing dosage to the heart. Modulation of diet and exercise has also been shown to be potentially cardioprotective. In mice, increased exercise training has been shown to be protective particularly against acute anthracycline cardiotoxicity and may also protect against chronic effects [51]. Meanwhile, rats fed with a high-fat diet show an increased sensitivity to doxorubicin that may be due to preexisting cardiac stress [52], suggesting that restricting diet or increasing exercise to improve overall cardiac health may reduce cardiotoxicity caused by anthracyclines.

9.2.5 Conclusions Although recent studies have significantly advanced our understanding of anthracycline-induced cardiotoxicity, many questions still remain. The search for human genetic variants, the use of cell culture and animal models to probe specific mechanisms, and the preclinical and clinical studies of treatments that may be cardioprotective or sensitizing have so far yielded strong results that are just beginning to make sense together. Since the cardiac damage caused by anthracyclines is irreversible, clinically relevant, and potentially fatal, the urgency of this research is not

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diminishing. Reducing the incidence of anthracycline cardiotoxicity through better drug development, cardioprotective strategies, and modulation of treatment based on genetic risk will improve outlook for many cancer survivors.

9.3 Mitoxantrone Mitoxantrone is a broad-spectrum anticancer drug with a similar structure to anthracyclines called an anthraquinone. It is a DNA intercalating agent and a ­topoisomerase II inhibitor with similar antitumor mechanisms to anthracyclines [53]. Phase I and II trials for mitoxantrone revealed incidents of cardiac failure and arrhythmias, including a 13% rate of LVEF decline and a 2.6% rate of heart failure. These ­reactions appeared to be dose dependent [54]. Mitoxantrone-induced cardiotoxicity, like anthracycline cardiotoxicity, can manifest as either an acute or chronic type [55]. An early randomized clinical trial comparing mitoxantrone to doxorubicin showed that although cardiac function declined on both drugs, treatment with doxorubicin caused a more accelerated drop. Risk of leaving the study due to cardiac events and risk of developing full-blown congestive heart failure were both also higher in doxorubicin-treated than mitoxantrone-treated patients [56]. A more recent trial again comparing mitoxantrone to anthracyclines in Hodgkin’s disease patients had the reverse result, demonstrating a significantly increased incidence of clinically relevant cardiac events and cardiac mortality on mitoxantrone compared with doxorubicin or epirubicin [57].

9.3.1 Mechanistic Insights Mitoxantrone causes similar ultrastructural pathology in the heart to that seen with anthracyclines: features of my­ofibrillar loss, sarcotubular dilation, and mitochondrial swelling [58]. These similarities suggest similar mechanisms to induce cardiac damage. Indeed, as discussed above, doxorubicin induces mitochondrial-mediated apoptosis pathways in cardiomyocytes. Similar apoptotic induction was observed with mitoxantrone [53]. Mitoxantrone has been shown to be a potent blocker of certain potassium channels, which causes a

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prolongation of the action potential in cardiomyocytes and may predispose to arrhythmias [58]. A comparison of cellular effects of doxorubicin vs. mitoxantrone showed that both drugs also delay calcium uptake by the sarcoplasmic reticulum (SR), but while doxorubicin also inhibits SR calcium release, mitoxantrone enhances SR calcium release [59]. Further studies need to be done to continue to clarify in what ways mitoxantrone cardiotoxicity is similar to and different from anthracycline cardiotoxicity, and to determine whether similar cardioprotective methods could be applied to mitoxantrone.

9.4 Tyrosine Kinase Inhibitors Tyrosine kinase inhibitors (TKIs) are targeted therapies in the form of either monoclonal antibodies or small molecule inhibitors that restrict cell signaling through kinases known to be important in cancer, for example, the ErbB2 receptor in breast cancer. Conceptually, by specifically inhibiting tyrosine kinases overexpressed in tumor cells, these therapies will be more effective against cancer cells and cause less damage to normal organs [60]. While these therapies are very effective for the treatment of cancer, some of them turned out to cause cardiotoxic effects. For multitargeted kinase inhibitors especially it is important to determine which pathways are causing the cardiac effects so better TKIs can be developed without those “off-target” effects [61].

9.4.1 Trastuzumab Trastuzumab is a monoclonal antibody against the ErbB2 receptor (also known as HER-2) approved for the treatment of ErbB2 positive breast cancer in 1998. ErbB2 is a member of the epidermal growth factor receptor family which includes EGFR and ErbB2-4. Approximately 1/3 of all breast cancers show a 10- to 100-fold increase in ErbB2 expression, and this phenotype is associated with poor prognosis [30]. Treatment with trastuzumab has significantly improved overall survival and disease-free survival rates in women with breast cancer [62]. Several studies have reported left ventricular dysfunction in up to 10% of patients and

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development of congestive heart failure in 1–4% of patients treated with trastuzumab alone [63–65]. Cumulative dose of the drug does not appear to be related to cardiac complications, and the effects are mostly reversible upon discontinuation of treatment [66]. No ultrastructural changes are observed in the myocardium of these patients, including no vacuolization or myocyte loss [64]. Risk factors for trastuzumab-induced cardiac dysfunction include older age, preexisting cardiovascular disease including coronary artery disease, diabetes, and valvular disease, and possibly prior radiation therapy to the left breast. Trastuzumab also causes synergistically increased toxicity when combined with anthracyclines (see anthracyclines section) or paclitaxel: up to 28% of women treated with anthracyclines and trastuzumab and 13% of women treated with paclitaxel and trastuzumab developed significant cardiac dysfunction [25, 67]. Paclitaxel, a taxane drug, causes a decrease in ERK1/2 phosphorylation, which leads to an increase in myofilament degradation; similar effects are seen with ErbB2 inhibitors. The combination of these two drugs increases diastolic calcium, shortens relaxation time, and reduces fractional shortening in heart tissue, suggesting an additive effect of cardiac dysfunction [68]. The question remains why cardiac tissue is sensitive to trastuzumab in spite of a relatively low level of ErbB2 receptor expression. ErbB2 was known to be required for formation of the heart, as knockout mice cause embryonic lethality due to defects in cardiac development. However, the role of ErbB2 signaling in the adult heart was unknown, until clinical cardiotoxicity associated with trastuzumab prompted a closer look. Conditional, cardiac-specific ErbB2 knockout mice have a dilated cardiomyopathy phenotype and exhibit excess mortality in response to pressure overload stress [69]. Trastuzumab has been shown to effectively phosphorylate ErbB2 in the human heart, and treatment over the course of weeks has been shown to induce breakdown of myocardial fibers and loss of the beating contractions [27]. Two hypotheses have been suggested. First, ErbB2 may be nonrandomly localized on the cell surface in such a way that it is easily targeted by trastuzumab. There is evidence that ErbB2 heterodimerizes with ErbB4 to signal in the heart and that both proteins localize specifically to the T-tubule. Alternatively, minor perturbations in ErbB2 signaling may be

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particularly devastating to cardiomyocytes. In chimeras where a subset of cells was ErbB2 negative, the entire heart was still unable to contract properly [27]. Another question is why only a small subset of patients develops cardiac dysfunction on trastuzumab if the ErbB2 pathway is so critical for cardiomyocyte function and survival. One hypothesis is that multiple “hits” are required: a heart with preexisting or concurrent stress, caused by prior heart disease or anthracycline treatment, would need to signal through ErbB2 more in order to maintain function [63]. Patients with these risk factors do show increased sensitivity to trastuzumab, supporting this theory. Another theory is that natural variability in expression of neuregulin genes NRG1 and NRG2 in the heart leaves some patients more vulnerable to trastuzumab-induced cardiac damage. One study showed that only a subset of patients absorbs the drug into the myocardium, and all of these patients developed cardiotoxicity [27, 70]. It is unknown what makes these patients more susceptible, but higher levels of ErbB2 expression or lower levels of ErbB4 expression (effectively mimicking higher levels of ErbB2) could also contribute to sensitivity. Despite a significant incidence of CHF as a result of trastuzumab treatment, cardiotoxicity caused by trastuzumab results in substantially lower morbidity and mortality compared with CHF due to anthracyclines [71]. The reversibility of cardiac dysfunction caused by trastuzumab was suggested by a study of 38 anthracycline-treated breast cancer patients who subsequently developed cardiac dysfunction (mean pre-treatment ejection fraction 61%; mean post-trastuzumab ejection fraction 45%) [64]. After discontinuation of trastuzumab and aggressive treatment with ACE inhibitors and beta blockers (BB), cardiac function returned to near-baseline levels in nearly all of these patients. Moreover, 25 of these patients were maintained on standard heart-failure therapy and were successfully rechallenged with trastuzumab without a subsequent decline in cardiac function.

9.4.2 Lapatinib Lapatinib is also an ErbB2 inhibitor, but is a small molecule rather than a monoclonal antibody targeting the EGF-receptor [61]. In a study of 3,700 patients, 60

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(2%) experienced cardiac events. No risk factors were identified, and cumulative dose was not related to incidence of cardiotoxicity. Cardiac events, including cardiac failure and palpitations, were generally reversible [72]. An analysis of multiple trials of patients treated with lapatinib for a variety of solid tumors showed that 1.6% of patients had a decline in the left ventricular ejection fraction, while 0.2% developed symptomatic congestive heart failure. The difference in cardiotoxicity between trastuzumab and lapatinib has not yet been explained. One possibility is that since trastuzumab is a monoclonal antibody, it may have immune-mediated effects on cardiomyocytes that are not replicated by the small molecule inhibitor lapatinib. Another explanation could be that these two drugs, despite targeting the same receptor, may trigger different intracellular signaling responses in cardiomyocytes, but not in cancer cells. A detailed molecular understanding of the differences between trastuzumab and lapatinib on cardiac function may provide key insights into the role of ErbB2 in cardiac function and may also provide insights into novel strategies for cardioprotection. A third possibility is that there is not a great inherent difference in cardiotoxicity, but that because of the findings with trastuzumab, patients were more carefully selected for lapatinib trials. For example, after the discovery of a severe increase in toxicity when trastuzumab and anthracyclines are used concurrently, patients receiving anthracycline treatment were screened more heavily for lapatinib trials [66].

9.4.3 Imatinib Imatinib was designed to inhibit Abl kinase, but also targets PDGF-receptors, c-Kit, and other pathways. It is used in the treatment of hematological malignancies and gastrointestinal stromal tumor (GIST). More than 80% of chronic myelogenous leukemia patients achieve full remission with imatinib treatment. Initial clinical trials, which likely excluded patients at high risk for cardiovascular disease, found no evidence of cardiotoxicity caused by imatinib. In 2006, however, a study was published on ten individuals who developed severe congestive heart failure during imatinib therapy. The pathology of these patients’ myocardiums revealed membrane whorls, pleomorphic mitochondria, and

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glycogen accumulation [73]. The same study reported that mice treated with imatinib developed cardiac dysfunction associated with activation of the ER stress response and resulting in histological findings similar to those observed in patients. The toxic effects of imatinib on cardiomyocytes were linked to inhibition of Abl kinase. Consistent with these findings, a modified form of imatinib, which has a specific reduction in activity against Abl kinase, produces substantially less cardiac toxicity in a murine model [74]. Despite these compelling findings, the incidence of clinically significant cardiomyopathy and heart failure attributable to imatinib appears to be low. A retrospective study of patients with CML treated with imatinib found that 1.7% of patients develop heart failure [75]. Risk factors included older age, prior treatment with anthracyclines or interferon, and prior history of cardiac disease or risk factors, but did not include increased dose of imatinib. Similarly, a retrospective study of gastrointestinal stromal tumor patients reported an incidence of heart failure and cardiomyopathy attributable to imatinib of less than 1% [76]. It is important to note that retrospective studies can underestimate the incidence of cardiotoxicity, particularly overlooking subclinical decreases in cardiac function. Nevertheless, based upon the existing data, the clinical significance of cardiotoxicity due to imatinib seems to be small. However, in light of preclinical findings suggesting that imatinib impairs aspects of the cardiac stress response, the long-term consequences of imatinib therapy warrant further, prospective study, particularly in patients with preexisting cardiovascular disease and when combined in anticancer regimens containing other established cardiotoxins.

9.4.4 Dasatinib and Nilotinib Dasatinib and nilotinib are both Abl kinase inhibitors developed for use in imatinib-resistant or -intolerant patients with leukemias [77, 78]. Dasatinib also inhibits Src family kinases, c-Kit, PDGF-receptors, and ephrin-A. In vitro studies suggested both drugs could potentially cause prolonged QT interval. Only 1% of patients treated with dasatinib, however, developed significant QT prolongation [78], whereas 3% of nilotinib treated patients develop significant QT

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prolongation [79]. QT prolongation should be ­managed by discontinuation of the drug or dose reduction. A clinically significant incidence of cardiomyopathy or heart failure associated with nilotinib or dasatinib has not been reported. Up to 35% of CML patients treated with dasatinib develop pleural effusions [80], with a significant number of such patients also developing pericardial effusions. However, these adverse effects do not appear to be the result of cardiac dysfunction. The etiology of such effusions appears to be multifactorial, due in part to generalized fluid retention, and possibly also attributable to immune-mediated effects [81]. Nilotinib is also associated with both pleural and pericardial effusions, albeit at a much lower frequency [77].

9.4.5 Sunitinib Sunitinib is an extremely promiscuous multiple tyrosine kinase inhibitor. In one study, sunitinib reacted with 18% of all kinases tested, a percentage that suggests the possibility of an extremely high number of kinases inhibited in  vivo [82]. Sunitinib activity against both VEGFR and PDGFR make it a highly antiangiogenic agent, which is the dominant mechanism of its antitumor effect. Sunitinib is approved for treatment of metastatic renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. Questions about the cardiac safety of sunitinib emerged from early clinical trials of the drug. In one study of patients with GIST, 10% of patients experienced left ventricular dysfunction compared with 3% treated with placebo [83]. Similarly, in one study, patients with metastatic renal cell carcinoma treated with sunitinib developed LVD 15% of the time [84]. In a study of 75 sunitinib-treated patients with no prior history of cardiac dysfunction, 19% of patients experienced a 15% or greater decline in ejection fraction, whereas 8% of patients developed cardiac dysfunction along with advanced heart failure symptoms [85]. Forty-seven percent of these patients experienced hyper­tension, including 17% with grade 3 or greater hypertension. In another study of metastatic renal cell carcinoma patients, 19% had substantial declines in left ventricular function with 7% experiencing left ventricular dysfunction and advanced heart failure. All of the heart failure patients also had grade

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3 hypertension [86]. In a referral-based study, six sunitinib-treated patients (3%) with no history of heart disease developed severe left ventricular dysfunction and heart failure associated with marked cardiac morbidity or mortality [87]. In each of these studies, the onset of cardiac toxicity from initiation of therapy was less than 6 months and was associated with the development of profound hypertension. Risk factors for development of sunitinib cardiotoxicity included history of hypertension and history of coronary artery disease. Studies reporting a higher incidence of hypertension also reported a higher percentage of patients developing heart failure [86]. Cardiotoxicity does not appear to be dose-dependent, and cardiac damage appears to be incompletely reversible after discontinuation of treatment [88]. Endomyocardial biopsies from patients with sunitinib cardiotoxicity showed hypertrophy and swollen mitochondria with membrane whorls. No inflammation or fibrosis was seen [85]. In the patients examined, there were no signs of ischemia or valvular damage, but histology showed loss of cellular mass with fragmented myocardial muscle bundles [89]. Few mechanistic studies have been done, but it appears hypertension may precede or contribute to sunitinib toxicity. Inhibition of PDGF-receptor signaling has been suggested as a possible mechanism for sunitinib cardiotoxicity. PDGF-receptor signaling stimulates myocyte growth in response to hypertensive stress [87]. However, endogenous PDGF signaling has not been shown to be cardioprotective, though overexpression of PDGF has [61]. A combination of hypertension and inhibition of key tyrosine kinases may be the cause of cardiotoxicity.

9.4.6 Sorafenib Sorafenib is also a multi-kinase inhibitor used in the treatment of renal cell and hepatocellular carcinoma, and is in trials for treatment of metastatic melanoma and non-small-cell lung cancer. Its targets include Raf-1, b-Raf, PDGF-receptor, VEGF-receptor, c-Kit, and Flt3 [90]. As Raf kinases and VEGF-receptor signaling are important in angiogenesis, sorafenib can be considered an antiangiogenic drug. A common side effect of all antiangiogenic drugs, including sorafenib, is hypertension [91]. Treatment with

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sorafenib reduces proliferation of vascular smooth muscle cells and increases apoptosis of these cells [90]. Its hypertensive effect is likely mediated thro­ ugh effects on vascular rarefaction and nitric oxide ­production associated with vascular endothelial dysfunction. Sorafenib also induces acute coronary symptoms, including myocardial infarction, in 2.9% of patients [92]. Some patients developed severe cardiac effects without prior history of heart disease or hypertension [93]. It may also cause a higher incidence of less dramatic cardiac events. Reinitiation of therapy after treatment of cardiovascular complications did not cause further problems [94]. In patients with poorly controlled hypertension, pressure load on the heart increases, and the normal response is to increase angiogenesis in the heart. Inhibition of angiogenesis by sorafenib may lead to heart failure in these patients [61, 95]. Sorafenib is significantly more toxic to cells relying entirely on mitochondria for energy generation. The drug has been shown to inhibit all complexes (I–V) in the mitochondrial electron transport chain. These experiments suggest that damages to mitochondrial energy metabolism processes might be a key cardiotoxic effect of sorafenib [92].

9.4.7 Bevacizumab Bevacizumab is a monoclonal anti-VEGF antibody approved to treat metastatic colon cancer, renal cell cancer, breast cancer, kidney cancer, and non-smallcell lung cancer. It is an angiogenesis inhibitor that also affects tumor vasculature in a way that improves delivery of other chemotherapeutic drugs and decreases pressure inside tumors. Like other angiogenesis inhibitors, it causes a significant percentage of patients to develop hypertension [96, 97]. Grade 3 or 4 hypertension is seen in 8–18% of patients, and the incidence appears to be dose-dependent. Risk of hypertension also increases with age over 75, African-American race, and specifically renal cell cancers [96]. This drug also causes an increase in severe cardiovascular complications. One study reported 2.1% of patients had myocardial infarctions, 2.5% had cerebrovascular accidents, 1.8% had hemorrhagic bleed in the gastrointestinal tract, 2.0% developed congestive heart

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failure, 3.0% developed angina, and 1.8% died suddenly over a 1 1/2-year period of bevacizumab treatment. Prior history of cardiovascular disease was a significant risk factor, and anthracycline treatment or radiation to the heart may also increase risk [98]. Many of these cardiovascular events were probably related to an increase in risk of arterial thromboembolism with bevacizumab treatment [5]. Age over 65 and prior history of thromboembolism are risk factors, but cumulative dose is not. Therapy with bevacizumab should be permanently discontinued in case of this type of complication. Thromboembolic effects may be mediated by a persistent inflammatory state that results from VEGF inhibition [96]. Mice with an endothelial-specific deletion of VEGF experience progressive endothelial degeneration leading to thrombosis [95]. The complication of hypertension is most likely due to inhibition of nitrous oxide synthase, causing vasoconstriction and a decrease in sodium ion excretion. These effects both raise blood pressure. Decreased capillary density, increased vascular resistance, disrupted balance of endothelin, and vascular rarefaction may also contribute to the hypertensive phenotype. Although most adult blood vessels were previously thought not to require VEGF signaling for maintenance, many recent studies refute that claim. Capillaries with endothelial fenestrations are most dependent on VEGF signaling and regress with VEGF inhibition [99]. This finding may help identify tumors most likely to respond to this therapy. Treatment with anticoagulants, ACE inhibitors, and calcium channel blockers may help to prevent the vascular side effects of bevacizumab.

9.4.8 Conclusions Contrary to the initial goals of targeted molecular therapeutics, it appears that tyrosine kinase inhibitors are frequently associated with a small but clinically important risk of severe cardiovascular complications. Prospective studies of cardiac function are needed for all of these drugs to determine the true incidence of hypertension, arrhythmias, cardiac ischemia, and congestive heart failure. Retrospective studies based on adverse event reports are likely to underestimate risks.

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As more targeted therapies are designed, researchers and clinicians should be aware of potential cardiotoxic effects. Many kinases have a known role in the heart, and as drugs are designed against them we should be especially careful. For example, loss of Jak1, Jak2, or Stat3 in the heart increases sensitivity to cardiac damage including that caused by anthracyclines. The drug lestaurtinib inhibits Jak2, and patients should be monitored for cardiac function during clinical tests of this drug. Another example is the drug perifosine, an inhibitor of Akt kinase, which has recently been identified as important for normal cardiac growth and response to stress. Vigilant monitoring for cardiotoxicity in patients treated with this agent may also be warranted.

9.5 Monoclonal Antibody Therapies 9.5.1 Alemtuzumab Alemtuzumab is a monoclonal antibody against CD52 and is used to treat chronic myelogenous leukemia. Initial infusion-related toxicity symptoms can include dyspnea and hypotension, but with a gradual increase of dose this reaction can be avoided [100]. Mycosis fungoides and Sezary syndrome are also sometimes treated with alemtuzumab, and one small study of this patient population reported an unacceptably high incidence of cardiac effects, including congestive heart failure, arrhythmias, deep venous thrombosis, severe hypotension, and vascular leak syndrome [101]. However, a subsequent retrospective analysis by another group identified no clinically significant cardiotoxicity in mycosis fungoides/Sezary syndrome patients treated with alemtuzumab [102]. CD52 is not expressed in cardiomyocytes or endothelial cells, so direct cardiovascular toxicity is unlikely, but rare incidences of cardiac effects may be mediated by inflammatory cytokine release leading to coronary spasm.

9.5.2 Rituximab Rituximab is a chimeric monoclonal antibody against CD20 used to treat multiple malignant and benign hematological conditions. Rituximab can cause severe

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infusion reactions that include hypotension and angioedema, with very severe reactions occurring in 1% of patients [103]. Rituximab is generally well tolerated with minimal cardiovascular toxicities, such as angina, which has been reported in less than 1% of infusions.

9.5.3 Cetuximab Cetuximab is a monoclonal anti-EGF-receptor antibody used to treat metastatic colon cancer either as a single agent or with irinotecan. It can cause a severe infusion reaction with hypotension in up to 3% of patients. This reaction can sometimes be fatal [103].

9.6 5-Fluorouracil and Capecitabine 5-Fluorouracil (5-FU) is an antimetabolite used to treat solid tumors of the breast, head, neck, and GI tract [95]. It inhibits thymidylate synthase in cancer cells and ultimately causes cell death [104], 5-FU is well known to cause myocardial ischemia and rarely myocardial infarction. The incidence of 5-FU cardiotoxicity has been reported in the range of 1.2–18%, depending on the treatment regimen and co-drugs. In a prospective analysis of patients receiving high-dose 5-fluoruracil by continuous infusion (600–1,000 mg/ m2/day), 7.6% experienced cardiac events during infusion [105]. Although the symptoms were transient in most of these patients, 2.2% of patients experienced cardiac death due to arrhythmias or circulatory collapse. More recently, a series of 427 patients receiving high-dose, continuous infusion 5-fluorouracil identified symptomatic cardiac toxicity with ischemic EKG changes in 17 treated patients (4%) during drug infusion [106]. Clinical improvement was noted in most patients with termination of infusion and administration of nitrates, but one patient died of an arrhythmia. Patients with established coronary artery disease may be at higher risk of developing myocardial ischemia during infusion of 5-FU [107]. Chest pain and EKG changes suggestive of myocardial ischemia have also been described in patients treated with capecitabine, an orally administered prodrug of 5-fluorouracil [108]. The nature and

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extent of capecitabine-induced myocardial ischemia may be similar to that of infusional 5-fluorouracil, although larger studies are needed to evaluate the risk of myocardial ischemia and infarction attributable to these two agents. Coronary vasospasm is an important mechanism leading to myocardial ischemia and/or infarction associated with 5-FU. In vitro experiments show that therapeutic levels of 5-FU cause a vasoconstriction effect in smooth muscle, possibly mediated by effects on protein kinase C and reversible by nitrate therapy [109]. Clinical research confirms that patients have a significantly decreased brachial artery diameter upon treatment with 5-FU. In addition, some reports suggest 5-FU can also cause non-ischemic cardiomyopathy and myocarditis [104], although this does not appear to occur commonly in clinical practice at usual dosage regimens.

9.7 Cyclophosphamide Cyclophosphamide is used in combination chemotherapy for several solid tumors and lymphomas, and is used at high dosages as a conditioning regimen prior to bone marrow transplantation. Although cyclophosphamide is well tolerated at lower dosages, LV dysfunction and CHF have been reported with high-dose regimens [110]. The myocardial injury due to highdose cyclophosphamide may be largely reversible [111], but significant morbidity and mortality have been seen in patients with cyclophosphamide-induced cardiac dysfunction [111]. Similarly, Quezado et  al. [112] have also reported a significant, dose-related incidence of CHF and arrhythmias in patients given ifosfamide. As with cyclophsphamide, ifosfamideinduced cardiac dysfunction appears to be transient and reversible. Pericarditis is another established cardiovascular toxicity associated with cyclophosphamide therapy [113]. The risk of cardiovascular toxicity due to cyclophosphamide increases with greater one-time doses of cyclophosphamide, but does not increase with cumulative dose [114]. Prior anthracycline treatment, prior irradiation to the heart, and a history of cardiovascular disease appear to increase the risk of cyclophosphamide cardiotoxicity [113–115].

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9.8 Cisplatin and Cisplatin-Based Combination Therapies

9.8.1 Toxicity with Combination Therapies

Cisplatin is an alkylating chemotherapy agent that produces interstrand DNA cross-links. Early case reports suggested that vascular ischemic events could be associated with cisplatin-based therapy: myocardial infarction, cerebrovascular accident, and hypertensive events were reported in young patients with no risk factors for cardiovascular disease [116–118]. A retrospective analysis of urothelial transitional cell carcinoma patients revealed vascular events in 12.9% of patients receiving cisplatin, including deep venous thrombosis (DVT), pulmonary embolisms, arterial thromboses, cerebrovascular accidents, and angina pectoris. Risk factors for these events included history of peripheral vascular disease or coronary artery disease and a large tumor size in the pelvis [119]. While older studies report a low rate of thrombosis, more recent studies show a significantly heightened risk on cisplatin-based therapies, including a particularly dangerous risk of grade 4 or 5 thrombotic events [120]. Treatment with prophylactic anticoagulation or calcium channel blockers may allow patients to continue use of cisplatin [116, 119], which is a very effective drug for the treatment of solid tumors. Although the exact mechanism of cisplatin-induced vascular toxicity is unknown, some indications and theories have been reported. Alterations to the clotting cascade affecting coagulability have been suggested as a possible mechanism particularly for thrombotic-type events [120]. Hypomagnesemia is reported to occur in 77–87% of patients after cisplatin-based chemotherapy, likely because cisplatin induces a tubular injury in the kidney that decreases the rate of reabsorption of magnesium. Lower Mg2+ concentration increases Ca2+ influx and results in constriction of the blood vessels. Elevation of plasma levels of von Willebrand factor (vWF) may also contribute to development of vascular disease. Cisplatin is known to stimulate endothelial cells to secrete increased levels of vWF [118]. This mechanism may be more frequently responsible for cerebrovascular accident or thrombosis, particularly in elderly patients, as these events typically occur earlier in the treatment course, while hypomagnesemia may contribute more to development of later events, which are predominantly myocardial infarctions without endovascular disease.

There are two commonly used cisplatin-based chemotherapy regimens for the treatment of cancers, in particular testicular seminoma and germ cell tumors: PVB (cisplatin, vinblastine, and bleomycin) and BEP (bleomycin, etoposide, cisplatin). Cisplatin-based combination chemotherapies have shown a “cure rate” for testicular cancer of over 80%. Both treatment courses have been associated with vascular toxicities, including development of Reynaud’s phenomenon in 37% of patients on either regimen [121]. Risk factors for Reynaud’s phenomenon include a cumulative dose of bleomycin, PVB treatment rather than BEP treatment, and hypertension [122]. Age, tumor histology, and other toxicities were not predictive factors [123]. Several other vascular events were seen more rarely: myocardial infarction [122, 124], angina pectoris [125, 126], cerebrovascular events [121], heart failure [126], major thromboembolic events (DVT, pulmonary embolisms (PE)) [127], and transient ischemia of the toes [125]. Digital ischemia occurred in 21% of patients treated without cisplatin compared with 41% treated with cisplatin [123]. Bleomycin is thought to be the most important drug in the pathogenesis of Reynaud’s phenomenon, while cisplatin is the most likely cause of the other vascular toxicities.

9.9 Other Chemotherapeutic Agents 9.9.1 Bleomycin Bleomycin is a glycoprotein used in the treatment of lymphomas, germ cell testicular cancer, and squamous cell cancers. In addition to peripheral vascular toxicities that have been reported with combination cisplatin/blemyocin treatment (described above), bleomycin has been associated with a 2.8% incidence of severe chest pain of unclear etiology [128]. It also has been associated with the development of acute pericarditis in a small subset of patients [128, 129]. In rare cases with young patients there have been reports of myocardial infarction or myocardial ischemia associated with bleomycin treatment [130].

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9.9.2 Irinotecan Used in the treatment of gastric and colorectal cancer, irinotecan may be associated with increased incidence of venous and arterial thromboembolic events. Eleven of 50 patients over two clinical trials developed drugrelated thromboembolism when treated with irinotecan or irinotecan plus bevacizumab (no difference in incidence between the two treatment groups) [131]. These findings have not been reported subsequently by other groups.

9.9.3 Cytarabine Cytarabine, also known as cytosine arabinoside, is a pyrimidine agonist used to treat acute myeloid leukemia [54]. Pericarditis is a rare side effect of this drug, mostly published in case reports [132, 133]. Cardiac tamponade has been reported to occur in conjunction with pericarditis in some patients [134], and capillary leak syndrome with pulmonary edema and pericardial effusion has also been reported [135]. Most published cases of pericarditis also report simultaneous pulmonary failure [135]. In all cases of pericardial disease appear to be directly related to the toxicity of cytarabine. Corticosteroid treatment may be an appropriate therapy for pericardial damage in these patients [132, 133].

9.9.4 Gemcitabine Gemcitabine is an antimetabolic drug, related to cytarabine, used in the treatment of solid tumors (most frequently breast and GI cancers). Original phase I trials of the drug used as a daily infusion caused severe hypertension, but the currently approved treatment regimen eliminates that side effect [136]. There have been case reports of gemcitabine-caused myocardial infarction [137, 138] and atrial fibrillation [136, 139]. The time frame to development of arrhythmic complications is within 12-24  h after infusion [140]. Gemcitabine has been reported to cause ventricular tachyarrhythmias of grade 1–4 in 2.3% of patients, cardiac dysfunction (with decline in LVEF) in 1.8% of

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patients, and mild pericarditis in 0.2% of patients [136]. It has also been reportedly associated with cases of thromboembolism [140]. The pathophysiology of these toxicities is unknown.

9.10 Microtubule-Altering Therapies 9.10.1 Vinca Alkaloids The vinca alkaloids are a class of microtubule-targeting drugs used to treat a wide array of solid and hematological cancers. Their mechanism of action is to disrupt microtubule assembly and arrest cells at metaphase [141]. There have been reports of hypertension, myocardial ischemia, myocardial infarction, and other vaso-occlusive disease with these compounds [54]. Vinorelbine is used to treat non-small-cell lung cancer, ovarian cancer, and breast cancer [142–144], and has been reported to cause an acute ischemic event or infarction during or very shortly after treatment [144]. A meta-analysis suggested an incidence of cardio­ toxicity of 1% with vinorelbine [145]. Vinblastine, vincristine, and vindesine are three other vinca alkaloids shown to cause repolarization disorders, precordial pain, acute ischemia, or infarction [144]. Risk factors for vinca alkaloid toxicity include female gender [145], prior cardiac history [145], prior irradiation [144], and prior anthracycline therapy [144]. Several mechanisms have been proposed, including direct toxicity to myofibrils [143], coronary vasospasm [142], progressive dissolution of the sarcoplasm and formation of membranous bodies [146], an affect on coagulation leading to arterial occlusion [144], and disorganization of cellular microtubules leading to impairment of metabolism and impairment of contractility [144]. Interestingly, several reports of vincristine interactions with doxorubicin have been published, some suggesting a higher incidence of ischemic toxicity [147], and others suggesting vincristine is cardioprotective against doxorubicin effects [141, 148]. Cell culture studies show vincristine increases myocyte survival signaling [141] and decreases oxidative stress and apoptosis [148]. More studies are needed to confirm and further probe these effects.

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9.10.2 Taxanes Taxanes work by stabilizing microtubules and preventing depolymerization [149], and are used to treat breast, ovarian, and non-small-cell lung cancers [5]. As described above, pre-clinical studies have suggested that combination taxane/anthracycline therapy may enhance formation of cardiotoxic anthracycline metabolites, potentially offering an explanation of excess cardiac toxicity observed when doxorubicin and paclitaxel were co-administered in bolus-dosing regimens to patients with metastatic breast cancer [22]. Importantly, a similar enhancement of clinical cardiotoxicity has not been observed when docetaxel is coadministered with doxorubicin [150]. However, taxanes can cause cardiotoxicity as single agents as well. Paclitaxel may cause sinus bradycardia in up to 30% of patients, although this rarely results in significant symptoms, while more serious arrhythmias such as conduction blocks or ventricular tachycardia can develop in up to 5% of treated patients [146, 151]. Complete heart block [152] and myocardial infarction [153] are rare but serious complications associated with taxane treatment. However, cardiac abnormalities caused by taxanes are typically asymptomatic and transient [153]. For these reasons, routine cardiac monitoring is not necessary for patients without preexisting cardiac risk factors, but monitoring is recommended for those with preexisting heart disease [152].

9.11 Hormone Therapies Breast cancer patients are often treated with some form of hormonal therapy in the adjuvant setting, depending upon the level of expression of hormonal receptors identified in tumor biopsy specimens. Such regimens usually consist of tamoxifen (an estrogen receptor antagonist) or aromatase inhibitors (which block the synthesis of estrogen). Several large trials have demonstrated an LDL cholesterol lowering effect of tamoxifen in breast cancer patients compared with placebo-treated or aromatase inhibitor-treated patients, suggesting a potential protective effect of tamoxifen [154]. Consistent with such an effect, women treated with tamoxifen had 50% fewer serious (grades 3–5) ischemic cardiac events compared with those treated the aromatase inhibitor letrozole [155]. However, in

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the same study, tamoxifen treatment was associated with a two-fold increase in thromboembolic events (p < 0.001) compared with letrozole-treated patients. As further evidence of a pro-thrombotic effect of tamoxifen, 1.2% of women with breast cancer treated with tamoxifen developed VTE compared with 0.5% of placebo treated controls [156]. The risk of thromboembolism due to tamoxifen is highest in older women and in the first 2  years of therapy, while the addition of chemotherapies to treatment regimens does not affect risk [156]. Hormonal therapy also has an important role in the treatment of patients with metastatic prostate cancer. Diethylstilbestrol (DES), a synthetic estrogen showed promise in the treatment of metastatic prostate cancer, but at higher dosages (5 mg/day), was found to result in an excess number of cardiovascular deaths compared to placebo, defined as death from myocardial infarction, stroke, heart failure, or pulmonary embolism [157]. Importantly, at lower dosages of DES (1 mg/day), a significant anticancer benefit is observed without an increase in cardiovascular deaths [158]. When used at this dosage, VTE remains the principal toxicity of DES and appears to occur in spite of prophylactic anticoagulation regimens that include low dose warfarin and aspirin [159]. The optimal prophylactic antithrombotic regimen in patients treated with DES has not yet been established. Another form of hormone therapy is androgen deprivation therapy for prostate cancer patients. This is achieved using several strategies, including orchiectomy, treatment with GnRH agonists, or treatment with antiandrogens. Patients treated with GnRh agonists had significantly more cases of diabetes, coronary artery disease, myocardial infarction, and sudden cardiac death than untreated patients [160, 161]. GnRh agonists increase fat mass and fasting insulin levels, and decrease insulin sensitivity [161], providing a mechanistic basis for this increased risk.

9.12 Other Miscellaneous Drugs 9.12.1 Bortezomib Bortezomib is a reversible proteasome inhibitor, resulting in cells accumulating poly-ubiquitylated proteins and eventually triggering apoptosis. It is used

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to treat multiple myeloma and non-small-cell lung cancer [162]. A 2007 study revealed an unexpected increase of cardiac complications in patients with multiple myeloma or non-Hodgkin’s lymphoma on bortezomib alone or in combination. Eight of 69 patients in the study developed serious cardiac effects, including heart failure and arrhythmias, requiring hospitalization or pacemaker implantation [163]. In contrast, the incidence of cardiac events in a large, phase III trial comparing bortezomib with dexamethasone for the treatment of multiple myeloma did not identify an excess of cardiac toxicity in the bortezomib-treated group and reported an incidence of heart failure of 2% in both treatment arms [164]. Since routine cardiac monitoring (e.g., echocardiography, electrocardiography, or clinical assessment by a cardiologist) was not mandated in this trial, the incidence of cardiac toxicity due to bortezomib may be underestimated. Importantly, the incidence of fatigue (a nonspecific symptom of cardiac failure) was significantly greater in the bortezomib-treated group despite a superior objective anticancer response compared with dexamethasone. Thus, the clinical significance of cardiac toxicity due to bortezomib remains unclear and will only be resolved with a prospective study with close cardiac monitoring. Cardiac toxicity due to bortezomib and other proteosome inhibitors is mechanistically plausible. The ubiquitin-proteasome system is crucial for the proper regulation of protein degradation within cardiomyocytes, and abnormalities in the proteasomal pathways and accumulation of damaged proteins are well recognized in several forms of cardiac failure [164]. In addition, a number of pre-clinical studies have linked proteosome inhibition with impaired protein quality control in the vascular endothelium, leading to accelerated atherosclerotic lesion formation [165, 166]. While the clinical significance of these findings is being explored, patients being treated with bortezomib who have preexisting heart disease or significant atherosclerotic risk factors should be closely monitored and receive therapies designed to reduce their cardiovascular risk.

9.12.2 Thalidomide Thalidomide, though most well known for its teratogenic effects, is currently in use for treatment of many solid organ and hematological cancers,

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particularly multiple myeloma. Thalidomide is an antiangiogeneic therapy that inhibits TNFa and modulates the immune system [167]. It has been linked with high incidences of deep venous thrombosis – up to 58% of patients experience an event in some drug combinations. More commonly reported incidences range from 12% to 20% [95]. Lower extremity thrombosis and pulmonary embolism are the most common manifestations, but cerebral venous sinus thrombosis, unstable angina, myocardial infarction, and stroke have also been reported [167]. Possible mechanisms of this adverse effect include inhibition of Cox2, overstimulation of immune response, and modulation of adhesion molecules [95]. Thalidomide acts directly on vascular endothelial cells, particularly those that have been previously damaged [167]. A structural analog of thalidomide, lenalidomide, is associated with similar toxicity. Both drugs are recommended to be used with prophylactic anticoagulant therapies [95].

9.12.3 Interferon-a High-dose interferon is used to treat cutaneous melanoma and other malignancies [168]. Two studies (one of Kaposi’s sarcoma patients and one of chronic myelogenous leukemia) both revealed increased rates of cardiomyopathy associated with interferon therapy [88]. The most common adverse effects reported are transient hypotension, atrial extrasystoles, and suptraventricular arrhythmias, but lethal arrhythmias, myocardial infarction, and dilated cardiomyopathy have also been described [168]. Reported incidence of arrhythmias is up to 20% [54], but incidence of other cardiac effects may be underreported due to similarity of symptoms with more common interferon side effects [88]. Pathology of interferon-treated myocardium shows no myocyte necrosis or anticardiac antibodies, with ultrastructural findings of endothelial tubuloreticular structures (this is an interferon signature) [88]. Interferon may damage endothelial cells, thicken capillary walls, and induce deposition of immune complexes. An inflammatory mechanism has been proposed to play a role in interferon cardiomyopathy [88, 168]. The most effective treatment of cardiac complications is discontinuation of interferon therapy [88].

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9.12.4 Arsenic Trioxide Arsenic trioxide is an effective treatment for relapsed or refractory acute promyelocytic leukemia, but it can cause cardiotoxicity usually manifesting as QT prolongation [169]. Arsenic prolongs action potential duration in the heart, which can also lead to tachyarrhythmias or sudden death [170]. Patients can also develop torsades de pointes or vascular leak syndrome [171]. The toxicity profile in children is similar to that in adults [171], with up to 63% of patients experiencing QT prolongation [54]. Risk factors for development of conduction abnormalities include hypomagnesaemia, hypokalemia, and hypocalcaemia [171]. Prior chemotherapy-induced cardiac damage may also contribute to increased incidence of cardiotoxicity [170]. Patients treated with arsenic who develop QT prolongation should be monitored for arrhythmias, and any electrolyte imbalances in these patients should be corrected before proceeding with therapy [172]. Possible mechanisms of arsenic cardiotoxicity include alterations in DNA methylation and repair, generation of reactive oxygen species, changes in cardiac ion channels, and apoptosis [169]. Apoptosis has been observed in a cell culture model of arsenic cardiotoxicity with caspase-3 activation, intracellular calcium overload, and increased reactive oxygen species [173]. Inhibition of caspase-3, or treatment with vitamin E or verapamil (both antioxidants) alleviated the apoptotic phenotype in this model, suggesting a possible cardioprotective mechanism [173]. Resveratrol, an antioxidant with antiapoptotic and antiarrhythmic effects, was also cardioprotective: concurrent treatment prevented QT prolongation, decreased myocardial injury, inhibited production of reactive oxygen species, and reduced the number of apoptotic cells [169].

9.12.5 IL-2 Interleukin-2 is used at high doses to treat metastatic melanoma and renal cell carcinoma [174]. Hemo­ dynamic alterations including severe hypotension and tachyarrhythmias are frequently observed adverse effects of IL-2 [175]. Treatment-related deaths occur in only 1.5% of patients, but serious complications including myocardial ischemia and myocarditis have

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been reported [176]. Histopathologic analysis suggests a diffuse lymphocytic and eosinophilic form of myocarditis with myocyte necrosis [177]. Capillary leak syndrome, which causes vascular permeability and hypotension, is observed in the majority of IL-2 patients, with vasopressor treatment required in 30–50% [178]. Case reports of more rare cardiotoxicities include global myocardial dysfunction [179], regional aneurysmal and dyskinetic cardiomyopathies [175], and acute myocardial infarction [176]. In addition to an inflammatory cardiomyopathy, direct myocardial toxicity may be due to myocardial stunning accompanied by excessive production of nitric oxide [175]. In an animal model, IL-2 treatment caused myocyte vacuolization, myofibrillar loss, swelling of endothelial cells, migration of lymphocytes into the interstitium, and interstitial hemorrhage and edema [180]. These results suggest that IL-2 activates lymphocytes that first attack endothelial cells, then cardiac myocytes, causing lesions in both cardiac vessels and the myocardium itself [180].

9.13 Cardiotoxicity as a Discovery Platform The value of studying cardiotoxic drugs is not limited to identifying the mechanisms of cardiotoxicity itself. Cardiotoxic effects of molecularly targeted anticancer therapies can shed light on the function of signaling pathways whose role in regulating cardiovascular function was previously unknown. Following such a discovery paradigm, researchers can discover new pathways that are important to the maintenance of adult human cardiac structure and function. Eventually this information may lead not just to better therapeutic strategies for cancer patients with cardiotoxicity, but also to therapies for diseases like cardiomyopathies and ischemic heart disease that are among the most common causes of death in our society. For example, as described above, the monoclonal anti-ErbB2 antibody trastuzumab was found to cause cardiotoxic effects, particularly when combined with anthracyclines. This result was surprising when it first appeared in the clinical trial data because previously ErbB2 was known to be required for embryonic heart development, but expression was thought to be too low

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to be relevant in the adult heart [210]. Recognition of trastuzumab’s cardiotoxicity led to the development of a conditional cardiac-specific knockout mouse model of ErbB2, which has a progressive dilated cardiomyopathy phenotype, and these mice also are more sensitive to anthracycline treatment than wild-type mice [181]. Pressure overload in the rat heart leads to decreased levels of ErbB2 signaling as hypertrophic responses develop into cardiomyopathy, suggesting a protective role of this signaling pathway [27]. Further work on these mice and their cells revealed an important role for ErbB2 signaling in cardiomyocyte survival and mitochondrial function [182]. More recent functional studies have concluded that impaired ErbB2-neuregulin signaling does not consistently lead to apoptosis in vivo, but suggests an interaction instead with neurohormonal regulatory systems. Neuregulin synthesis by endothelial cells appears to be regulated by epinephrine, angiotensin, endothelin, and mechanical stress [183]. Treatment with neuregulin (the ErbB ligand) prolongs survival in several animal models of cardiomyopathies [184]. Clinical trials testing the efficacy of neuregulin as a therapeutic for patients with cardiomyopathy are currently ongoing. The initial evidence of neuregulin-ErbB2 signaling as a cardioprotective pathway emerged as a result of the surprising finding of cardiotoxicity from the antiErbB2 antibody in trastuzumab. The result is a better understanding of the heart itself and a new potential therapeutic target for cardiomyopathy in humans. This same paradigm can be applied to cardiotoxicity caused by other targeted therapies to build a more complete picture of cardioprotective signaling pathways and further our understanding of human heart disease.

9.14 Conclusion Treatment of cardiovascular complications of cancer or cancer therapies first relies on identifying the underlying problem. Excluding nontreatment-related causes of cardiovascular damage suggests that cardiotoxicity of one or more agents in the patient’s treatment regimen is at fault. For many of these drugs, cardiac effects are reversible upon discontinuation of treatment, so this should be the first step undertaken. After

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resolving or stabilizing the cardiovascular disease, rechallenge with the same drug or a change in the treatment regimen can be considered depending on the circumstances. Treatment of cardiomyopathy caused by cardiotoxicity should begin with preventative treatments in those patients at greatest risk. In patients undergoing treatment with potentially cardiotoxic anticancer therapy, we propose that such patients can be classified as stage A patients (at risk for heart failure) per the recently established guidelines for the prevention and treatment of heart failure from the American Heart Association/ American College of Cardiology [60] (see Fig.  9.1). Such guidelines recommend patients receive aggressive treatment for risk factors for cardiovascular disease including diabetes, smoking, hypertension, and hyperlipidemia [49]. Patients who develop asymptomatic cardiac dysfunction (the stage B patient) should be treated with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or beta-blockers [185, 186]. More aggressive drug and/or device treatments are reserved for patients with symptomatic cardiac dysfunction [1]. For patients with myocardial ischemia, treatment with calcium channel blockers or nitrates can be helpful. Prophylactic vasodilators are sometimes used when rechallenging with a drug that produced ischemia, but may not always be effective [187]. It can be especially challenging to treat acute myocardial infarctions in cancer patients, since many cancer therapies cause a high rate of adverse effects like thrombocytopenia that significantly complicate or prevent use of typical therapies [142]. Aspirin therapy does provide a substantial survival benefit, even in patients with thrombocytopenia, so its use is recommended in most patients with acute myocardial infarction [188], and statin therapy is also usually safe and effective in these patients [189]. For most other cardiac effects, including arrhythmias, QT prolongation, hypertension, and thromboembolism, there are limited specific guidelines for treatment in patients with cancer [190]. Caution and monitoring in patients with higher than average risk are the best ways to detect cardiovascular complications. Treatment should be undertaken as with any other patient, but with an awareness of the patient’s other disease and treatment-based toxicities in mind. Cardiovascular diseases are a considerable worry for cancer survivors. As reviewed here, many cancer

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At Risk for Heart Failure STAGE A At high risk for HF but without structural heart disease or symptoms

e.g., Patients with: -hypertension -atherosclerotic disease -diabetes -obesity -metabolic syndrome or Patients -using cardiotoxins -with FHx CM

THERAPY GOALS -Treat hypertension -Encourage smoking cessation -Treat lipid disorders -Encourage regular exercise -Discourage alcohol intake, illicit drug use -Control metabolic syndrome DRUGS -ACEI or ARB in appropriate patients (see text) for vascular disease or diabetes

Structural heart disease

Heart Failure

STAGE B Structural heart disease but without signs or symptoms of HF.

STAGE C Structural heart disease with prior or current symptoms of HF.

e.g., Patients with: -previous MI -LV remodeling including LVH and low EF -asymptomatic valvular disease

e.g., Patients with: -known structural heart disease and -shortness of breath and fatigue, reduced exercise tolerance

Development of HF symptoms

STAGE D Refractory HF requiring specialized interventions.

Refractory symptoms of HF at rest

e.g., Patients who have marked symptoms at rest despite maximal medical therapy (e.g., those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions)

THERAPY THERAPY GOALS -All measures under Stage A DRUGS -ACEI or ARB in appropriate patients (see text) -Beta-blockers in appropriate patients (see text) DEVICES IN SELECTED PATIENTS -Implantable defibrillators

GOALS -All measures under Stages A and B -Dietary salt restriction DRUGS FOR ROUTINE USE -Diuretics for fluid retention -ACEI -Beta-blockers DRUGS IN SELECTED PATIENTS -Aldosterone antagonist -ARBs -Digitalis -Hydralazine/nitrates DEVICES IN SELECTED PATIENTS -Biventricular pacing -Implantable defibrillators

THERAPY GOALS -Appropriate measures under Stages A, B, C -Decision re: appropriate level of care OPTIONS -Compassionate end-oflife care/hospice -Extraordinary measures • heart transplant • chronic inotropes • permanent mechanical support • experimental surgery or drugs

Fig. 9.1  AHA Guidelines for the Classification and Treatment of Congestive Heart Failure. Stages in the development of heart failure/recommended therapy by stage. Cancer patients treated with potentially cardiotoxic chemotherapy (reviewed within) are at risk for the development of heart failure and should be treated according to the treatment recommendations for stage A patients.

Reprinted with permission from the American Heart Association. HF heart failure, FHx CM family history of cardiomyopathy, ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin receptor blocker, MI myocardial infarction, LVH left ventricular hypertrophy, EF ejection fraction

therapies cause significant cardiotoxicity, and in some cases those effects may be underestimated due to the nature of clinical trials. Clinicians should be watchful for early signs or symptoms of cardiotoxicity in their patients. Prevention and treatment of these adverse effects is crucial, and more work needs to be done to define methods of prevention and optimize treatment in the specific population of cancer survivors. Research into the mechanisms of cardiotoxicity will help better identify prevention strategies, as well as enhancing our scientific knowledge of how these drugs work.

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